Cyanoguanidine compounds

ABSTRACT

A cyanoguanidine compound of the following formula:                    
     is disclosed. A cyanoguanidine compound of the present invention possess a high specificity for tumor cells. Also disclosed are methods for preparing a cyanoguanidine compound.

CROSS REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 USC §119(e), this application claims the benefit of priorU.S. provisional applications 60/128,665, filed Apr. 9, 1999;60/148,429, filed Aug. 11, 1999; and 60/151,808, filed Aug. 31, 1999.

BACKGROUND

Cancer remains a formidable disease with a high mortality rate intoday's society. Indeed, cancer is second only to cardiovascular diseaseas a cause of death, killing one out of four people in developedcountries.

Cancerous tumors commonly originate from normal cells which transforminto malignant cells or tumors. The initial tumor growth may be slow andthus may be difficult to detect. The growth often becomes moreaggressive and invasive with time, eventually spreading throughout thewhole body and resulting in death.

Cancer treatment usually includes immunotherapy, surgery, radiation,hormones, and chemotherapy. In the past forty years, cancer chemotherapyhas truly revolutionized the treatment of malignant tumors. Curativetreatment has been discovered for many of the cancers that affectchildren and young adults, including acute lymphocytic leukemia,Hodgkin's disease, testicular carcinoma, and many others. However,despite being a powerful method of treating cancer, chemotherapy doessuffer from a few problems. The most prominent problem is the lowspecificity of the anticancer agents. That is, most anticancer agents donot adequately distinguish normal cells from cancer cells. As a result,they often carry undesirable serious side effects. Such limitations ofconventional chemotherapies underscore the urgent need for newanticancer agents with high antitumor activities and specificity to thecancerous cells.

SUMMARY

An aspect of this invention relates to compounds of formula (I):

R¹ is 3-pyridyl, 4-pyridyl, or quinolinyl, optionally substituted withalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl,alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino,aminosulfonyl, sulfonic acid, or alkylsulfonyl. Each of R² and R³,independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, thioalkyl,aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino,or aminocarbonyl. L¹ is —X¹—Y¹—X²—. Each of X¹ and X², independently, isa bond, or a C₁₋₆ alkylene chain optionally containing a double bond ora triple bond and further optionally substituted with alkoxy, hydroxyl,halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy,alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, oraminocarbonyl. Y¹ is —O—, —S—, —SO—, —SO₂—, —N(R^(a))—, —CO—,—N(R^(a))—CO—, —CO—N(R^(a))—, —N(R^(a))—CO—CO—, —N(R^(a))—SO₂—,—SO₂—N(R^(a))—, —N(R^(a))—CO—O—, —O—CO—N(R^(a))—,—N(R^(a))—CO—N(R^(b))—, —N(R^(a))—CS—N(R^(b))—CO—, —CO—, —CO—N(R^(a))—CS—N(R^(b))—, —O—CO—, —CO—O—, —O—SO₂—, —SO₂—O—,—O—S—CO—N(R^(a))—, —N(R^(a))—CO—S—O—, —O—CO—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond.Each of R^(a) and R^(b), independently, is hydrogen, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl. R⁴ is aryl, optionally substituted with alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino,aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl,formyl, oxo, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino,aminosulfonyl, sulfonic acid, or alkylsulfonyl. L₂ is —X³—Y²—X⁴— inwhich each of X³ and X⁴, independently, is a bond, or a C₁₋₆ alkylenechain optionally containing a double bond or a triple bond and furtheroptionally substituted with alkoxy, hydroxyl, halo, carboxyl, amino,nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl,alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl. Y² is —O—,—S—, —SO—, —SO₂—, —N(R^(c))—, —CO—, —N(R^(c))—CO—, —CO—N(R^(c))—,—N(R^(c))—CO—CO—, —N(R^(c))—SO₂—, —SO₂—N(R^(c))—, —N(R^(c))—CO—O—,—O—CO—N(R^(c))—, —N(R^(c))—CO—N(R^(d))—, —N(R^(c))—CS—N(R^(d))—CO—,—CO—N(R^(c))—CS—N(R^(d))—, —O——CO—, —CO—O—, —O—SO₂—, —SO₂—O—,—O—S—CO—N(R^(c))—, —N(R^(c))—CO—S—O—, —O—CO—O—,—CO—N(R^(c))—S—CO—N(R^(d))—, —N(R^(c))—CO—S—N(R^(d))—CO— or a bond. Eachof R^(c) and R^(d), independently, is hydrogen, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl. R⁵ is cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, or heteroaryl, optionally substituted withalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy,aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxyalkyl aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo,aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl,aminocarbonyloxy, or alkyloxycarbonylamino. Note that each of Y¹ and Y²is not a bond simultaneously, and that when neither Y¹ nor Y² is a bond,at least one of X², R⁴, and X³ is not a bond.

Another aspect of this invention relates to cyanoguanidine compoundshaving the formula (I) as depicted above. R¹ is 3-pyridyl, 4-pyridyl, orquinolinyl, optionally substituted with alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy,hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl,alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino,aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, oralkylsulfonyl. Each of R² and R³, independently, is hydrogen, alkyl,alkoxy, hydroxylalkyl, thioalkyl, aminoalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkylcarbonyloxy, alkyloxycarbonyl,alkylcarbonyl, alkylcarbonylamino, or aminocarbonyl. L¹ is —X¹—Y¹—X²—.Each of X¹ and X², independently, is a bond, or a C₁₋₆ alkylene chainoptionally containing a double bond or a triple bond and furtheroptionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl,halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy,alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, oraminocarbonyl. Y¹ is —O—, —S—, —SO—, —SO₂—, —N(R^(a))—, —CO—,—N(R^(a))—CO—, —CO—N(R^(a))—, —N(R^(a))—CO—CO—, —N(R^(a))—SO₂—,—SO₂—N(R^(a))—, —N(R^(a))—CO—O—, —O—CO—N(R^(a))—,—N(R^(a))—CO—N(R^(b))—, —N(R^(a))—CS—N(R^(b))—CO—,—CO—N(R^(a))—CS—N(R^(b))—, —O—CO—, —CO—O—, —O—SO₂—, —SO₂—O—,—O—S—CO—N(R^(a))—, —N(R^(a))—CO—S—O—,—O—CO—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, N(R^(a))—CO—S—N(R^(b))—CO—, or a bond. Eachof R^(a) and R^(b), independently, is hydrogen, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl. R⁴ is a bond, or cycloalkyl, cycloalkenyl, or aryl,optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl,carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkylcarbonyloxy,alkyloxycarbonyl, alkylcarbonyl, formyl, oxo, alkylcarbonylamino,aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, oralkylsulfonyl. L² is —X³—Y²—X⁴—. Each of X³ and X⁴, independently, is abond, or a C₁₋₆ alkylene chain optionally containing a double bond or atriple bond and further optionally substituted with alkyl, alkenyl,alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl,alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl,formyl, alkylcarbonylamino, or aminocarbonyl; and Y² is —O—, —S—, —SO—,—SO₂—, —N(R^(c))—, —CO—, —N(R^(c))—CO—, —CO—N(R^(c))—, —N(R^(c))—CO—CO—,—N(R^(c))—SO₂—, —SO₂—N(R^(c))—, —N(R^(c))—CO—O—, —O—CO—N(R^(c))—,—N(R^(c))—CO—N(R^(d))—, —N(R^(c))—CS—N(R^(d))—CO—,—CO—N(R^(c))CS—N(R^(d))—, —O—CO—, —CO—O—, —O—SO₂—, —SO₂—O—,—O—S—CO—N(R^(c))—, —N(R^(c))—CO—S—O—, —O—CO—O—,—CO—N(R^(c))—S—CO—N(R^(d))—, —N(R^(c))—CO—S—N(R^(d))—CO—, or a bond.Each of R^(c) and R^(d), independently, is hydrogen, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl. R⁵ is a cyclic moiety having 12-20 ring atoms, optionallysubstituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy,aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxyalkyl, aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo,aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl,aminocarbonyloxy, or alkyloxycarbonylamino. When neither one of Y¹ andY² is a bond, at least one of X², R⁴, and X³ is not a bond.

Set forth below are some examples of a cyanoguanidine compounds of thisinvention: 5-dimethylamino-naphthalene-1-sulfonic acid(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-amide,naphthalene-1-sulfonic acid(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-amide,N-(4-(N′-cyano-N″-pyridin-4-yl-guanidino-methyl)-phenyl)-3-trifluoromethyl-benzenesulfonamide,2,4,6-trimethyl-N-(4-(N′-cyano-N″-pyridin-4-yl-guani-dinomethyl)-phenyl)-benzenesulfonamide,4-chloro-N-(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-benzenesulfonamide,N-{2-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethoxy]-ethyl}-N′-cyano-N″-pyridin-4-yl-guanidine,andN-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethyl]-N-[2-(N′-cyano-N″-pyridin-4-yl-guanidino)-ethyl]-acetamide.

Note that two adjacent substituents on the pyridine ring can jointogether to form a 4- to 7-membered cyclic moiety together with the twocarbon atoms to which the substituents are bonded. The cyclic moiety canbe cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl,or heteroaryl. For example, a quinolinyl is formed when the cyclicmoiety is a benzene. Heteroatoms such as nitrogen, oxygen, and sulfurcan be included in the cyclic moiety.

An N-oxide derivative or a salt of each of the cyanoguanidine compoundsdescribed above is also within the scope of this invention. For example,the nitrogen ring atom of the pyridine ring can form an oxide in thepresence of a suitable oxidizing agent such as m-chloroperbenzoic acidor H₂O₂. A pharmaceutically acceptable salt can be formed when acyanoguanidine compound of this invention reacts with an inorganic ororganic acid. Some examples of such an acid include hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, and acetic acid. Examples of pharmaceutically acceptablesalts thus formed include sulfate, pyrosulfate bisulfate, sulfite,bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, decanoate, caprylate, acrylate, formate, isobutyrate,caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, and maleate.

It should be recognized that a cyanoguanidine compound of this inventionmay contain chiral carbon atoms. In other words, it may have opticalisomers or diastereoisomers. These isomers are all within the scope ofthis invention.

As used herein, alkyl is a straight or branched hydrocarbon chaincontaining 1 to 12 carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, 2-methylhexyl, 3-ethyloctyl, and4-ethyldecyl.

The terms “alkenyl” and “alkynyl” refer to a straight or branchedhydrocarbon chain containing 2 to 12 carbon atoms and one or more (e.g.,1-6) double or triple bonds, respectively. Some examples of alkenyl andalkynyl are allyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-butynyl,2-pentynyl and 2-hexynyl.

As used herein, a C₁₋₆ alkylene chain is a divalent hydrocarbon chaincontaining 1-6 carbon atoms. For example, a C₁ alkylene chain and a C₂alkylene chain refer to a methylene and an ethylene group, respectively.

By cycloalkyl is meant a cyclic alkyl group containing 3 to 8 carbonatoms. Some examples of cycloalkyl are cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, and norbornyl. Heterocycloalkyl is acycloalkyl group containing 1-3 heteroatoms such as nitrogen, oxygen, orsulfur. Examples of heterocycloalkyl include piperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrofuryl, and morpholinyl. Cycloalkenyl is acycloalkyl group containing one or more (e.g., 1-3) double bonds.Examples of such a group include cyclopentenyl, 1,4-cyclohexa-di-enyl,cycloheptenyl, and cyclooctenyl groups. By the same token,heterocycloalkenyl is a heterocycloalkyl group containing one or moredouble bonds.

As used herein, aryl is an aromatic group containing 6-12 ring atoms andcan contain fused rings, which may be saturated, unsaturated, oraromatic. Examples of an aryl group include phenyl, naphthyl, biphenyl,phenanthryl, and anthracyl. Heteroaryl is aryl containing 1-3heteroatoms such as nitrogen, oxygen, or sulfur and can contain fusedrings. Some examples of heteroaryl are pyridyl, furanyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, andbenzthiazolyl.

As used herein, a cyclic moiety is cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl. A cyclic moietycan also be fused rings and can be formed from two or more of thejust-mentioned groups. Examples of a cyclic moiety having fused ringsinclude fluorenyl, dihydro-dibenzoazepine, dibenzocycloheptenyl,7H-pyrazino[2,3-c]carbazole, or 9,10-dihydro-9,10-[2]buteno-anthracene.

Each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, or heteroaryl described herein is optionallysubstituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy,aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxyalkyl, aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo,aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl,aminocarbonyloxy, or alkyloxycarbonylamino.

Note that an amino group can be unsubstituted, mono-substituted, ordi-substituted. It can be substituted with groups such as alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl. Halo refers to fluoro, chloro, bromo, or iodo.

Cyanoguanidine compounds of this invention possess an unexpectedly highspecificity for tumor cells. Other features or advantages of the presentinvention will be apparent from the following detailed description ofseveral embodiments, and also from the appending claims.

DETAILED DESCRIPTION

A cyanoguanidine compound of this invention can be prepared by a numberof methods. Two methods (1) and (2) are described herein. Each of thememploys a common starting material,S-methyl-N-cyano-N′-pyridylisothiourea or compound (A) as shown in thetwo schemes below. For preparation of this starting material, see Schouet al., Bioorganic & Medicinal Chemistry Letters, 7(24), 3095-3100(1997).

In the synthetic scheme of method (1), the definitions of R¹, R², R³,R⁴, R⁵, X¹, X², X³, X⁴, Y¹, and Y² have been provided above. Compound(A) is first coupled with a primary amine or secondary amine,NH(R³)—X¹—Y^(1′), to yield an intermediate, compound (B), which is thencoupled with X^(2′)—R⁴—X³—Y²—X⁴—R⁵ to yield the desired cyanoguanidinecompound. Examples of secondary amines include cyclic amines such aspiperidinyl or piperazinyl. Note that Y^(1′) and X^(2′) arefunctionalities which, upon reacting with each other, yield moieties ofY¹ and X², respectively. For example, if the desired yl moiety is anamide, it can be formed by reacting an amine group (Y^(1′)) with acarboxyl group (X^(2′)) in the presence of a common coupling reagentsuch as benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (BOP) orO-benzo-triazol-1-yl-N,N,N,N′-tetramethyluronium hexafluorophosphate(HBTU). The following scheme also includes exemplary conditions in whichfive other Y¹ moieties, i.e., sulfonamide, urea, oxygen, amino, andsulfur linkages, are formed.

Alternatively, compound (A) can be first coupled with NH(R³)—X¹—Y—X²—R⁴—X³—Y^(2′) to form an intermediate, which then reacts withX^(4′)—R⁵ to form a cyanoguanidine compound of this invention. Similarto Y^(1′) and X^(2′), Y^(2′) and X^(4′) are functionalities, uponreacting with each other, yield moieties of Y² and X⁴, respectively.

The scheme below shows yet another method of preparing a cyanoguanidinecompound of this invention. According to this scheme, NH(R³)—X¹—Y^(1′)first reacts with X^(2′)—R⁴—X³—Y²—X⁴—R⁵ to form an intermediate NH(R³)—X¹—Y¹—X²—R⁴—X³Y²—X₃Y²—X⁴—R⁵, which, in turn, is coupled with compound(A) to form a cyanoguanidine compound of this invention.

Compounds of formula (I) in which R⁴ is a nitrogen-containing cyclicmoiety, e.g., piperidinyl or imidazolyl, can be prepared by reactingNH(R³)—X¹—Y¹—X²—R⁴ with X^(3′)—Y²—X⁴—R⁵ to form an intermediateNH(R³)—X¹—Y¹—X²—R⁴—X³—Y²—X⁴—R⁵ before further reacting withS-methyl-N-cyano-N′-pyridylisothio-urea or compound (A). See, e.g.,Examples 7 and 8. The following scheme illustrates yet another method toprepare the intermediate NH(R³)—X¹—Y¹—X²R⁴—X³—Y²—X⁴—R⁵ where R⁴ is2,4-imidazolyl:

Note that appropriate protecting groups may be needed to avoid formingside products during the preparation of a cyanoguanidine compound. Forexample, the amino group of NH(R³)—X¹—Y^(1′) can be first protected by asuitable amino protecting group such as trifluoroacetyl ortert-butoxycarbonyl prior to coupling with X^(2′)—R⁴—X³—Y²—X⁴—R⁵. See,e.g., T. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley& Sons, Inc., New York (1981), for other suitable protecting groups.

A cyanoguanidine compound produced by the methods shown above can bepurified by flash column chromatography, preparative high performanceliquid chromatography, or crystallization.

A pharmaceutical composition containing an effective amount of one ormore cyanoguanidine compounds of this invention is also within the scopeof this invention. Some examples of tumors which can be treated by thispharmaceutical composition are leukemia, lung cancer, colon cancer, CNScancer, melanoma, ovarian cancer, cervical cancer, renal cancer,prostate cancer, and breast cancer. The use of such a cyanoguanidinecompound for the manufacture of a medicament for treating theabove-mentioned tumors is also within the scope of this invention. Stillanother aspect of this invention is a method of treating tumor byadministering to a patient a pharmaceutical composition containing aneffective amount of a cyanoguanidine compound of this invention or itsN-oxide derivative or salt. An effective amount is defined as the amountwhich is required to confer a therapeutic effect on the treated patient,and is typically determined based on age, surface area, weight, andcondition of the patient. The interrelationship of dosages for animalsand humans (based on milligrams per meter squared of body surface) isdescribed by Freireich et al., Cancer Chemother. Rep. 1966, 50,219. Bodysurface area may be approximately determined from height and weight ofthe patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals,Ardley, New York, 1970, 537. An effective amount of a cyanoguanidinecompound of this invention can range from about 1 mg/kg to about 150mg/kg. Effective doses will also vary, as recognized by those skilled inthe art, dependant on route of administration, excipient usage, and thepossibility of co-usage with other therapeutic treatments including useof other antitumor agents and radiation therapy.

The pharmaceutical composition may be administered via the parenteralroute, including orally, topically, subcutaneously, intraperitoneally,intramuscularly, and intravenously. Examples of parenteral dosage formsinclude aqueous solutions of the active agent, in a isotonic saline, 5%glucose or other well-known pharmaceutically acceptable excipient.Solubilizing agents such as cyclodextrins, or other solubilizing agentswell-known to those familiar with the art, can be utilized aspharmaceutical excipients for delivery of the therapeutic compounds.

A cyanoguanidine compound of this invention can be formulated intodosage forms for other routes of administration utilizing conventionalmethods. For example, it can be formulated in a capsule, a gel seal, ora tablet for oral administration. Capsules may contain any standardpharmaceutically acceptable materials such as gelatin or cellulose.Tablets may be formulated in accordance with conventional procedures bycompressing mixtures of a cyanoguanidine compound with a solid carrierand a lubricant. Examples of solid carriers include starch and sugarbentonite. The cyanoguanidine compound can also be administered in aform of a hard shell tablet or a capsule containing a binder, e.g.,lactose or mannitol, a conventional filler, and a tableting agent.

The antitumor activity of a cyanoguanidine compound of this inventioncan be evaluated by MTS colorimetric assay (see Example 149 below).Results obtained by using cell lines of various types of tumors arecompared with those obtained by using cell lines of normal cells in thisassay. Viability of the cells in each cell line is estimated bymeasuring the cellular conversion of a tetrazolium salt after incubatingthe cells in a solution containing a test cyanoguanidine compound in a96 well plate. IC₅₀ values obtained by using an identical test compoundon normal cells and cells of a particular tumor cell line are comparedand their ratio (IC_(50 normal cell)/IC_(50 cancer cell)) indicates thecancer selectivity of that test compound. The higher the ratio, thehigher the selectivity of the test compound towards that particular typeof cancer cell.

The antitumor activity of a cyanoguanidine compound of this inventioncan also be evaluated by in vivo testing, e.g., human tumor xenograftregression assays. Animals bearing established tumors are treated with atest compound for a three-week period. The growth of the tumors and thegeneral health of the animal are monitored during the three-weektreatment and for two more weeks after treatment to determine if tumorregrowth occurs. See Example 150 below.

The toxicity of a cyanoguanidine compound of this invention is evaluatedby preliminary sub-acute toxicity study and acute toxicity study. SeeExamples 151 and 152 below.

The following specific examples, which describe syntheses and biologicaltestings of cyanoguanidine compounds of this invention, are to beconstrued as merely illustrative, and not limitative of the remainder ofthe disclosure in any way whatsoever.

In the following examples, the cyanoguanidine compounds were purified byusing Gilson® preparative high performance liquid chromatography,equipped with a 306 pump and a WATERS BONDAPACK C18 column, eluted withmethanol/water or acetonitrile/water. ¹H Nuclear magnetic resonancespectra were recorded on a Varian Mercury 300 MHz spectrometer. ES massspectra were recorded on a Finnigan Navigator mass spectrometer.

Without further elaboration, it is believed that one skilled in the artcan, based on the description herein, utilize the present invention toits fullest extent. The following specific examples, which describedsyntheses, screening, and biological testing of various compounds ofthis invention, are therefore, to be construed as merely illustrative,and not limitative of the remainder of the disclosure in any waywhatsoever. All publications recited herein, including patents, arehereby incorporated by reference in their entirety.

EXAMPLE 1 9H-fluorene-9-carboxylic acid(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-amide(SBR-11-2727) was synthesized as follows

In a reaction flask under nitrogen with magnetic stirring1-cyano-2-methyl-3-pyridin-4-yl-isothiourea (0.35 g, 1.82 mmol) and4-aminobenzylamine (0.25 g 2.05 mmol) were suspended in ethanol (1.5mL). Triethylamine (0.19 g, 1.36 mmol) was added followed by(4-dimethylamino)pyridine (6 mg, 0.05 mmol). This reaction mixture washeated at 60° C. for 4 hours then cooled to room temperature. Theresulting solid was collected by filtration and washed with cold ethanol(10 mL) to give N-(4-amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidineas a white solid in 77% yield. ¹H NMR (DMSO-d₆, ppm): 9.43 (s, 1H), 8.38(d, 2H), 8.14 (s, 1H), 7.19 (d, 2H), 7.00 (d, 2H), 6.54 (d, 2H), 5.07(s, 2H), 4.03 (d, 2H) ESMS 289.0 (M+23).

N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (133 mg, 0.50mmol) and 9H-fluorene-9-carboxylic acid (105 mg, 0.50 mmol) weresuspended in N,N-dimethylformamide(1.0 mL).Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(232 mg, 0.52 mmol) was added followed by N,N-diisopropylethylamine(0.20 mL, 1.15 mmol). The reaction mixture was stirred at roomtemperature for 24 hours and then diluted with ethyl acetate (30 mL).This solution was washed with water (30 mL×2) and dried over anhydroussodium sulfate. The solvent was removed in vacuo to give the desiredproduct (102 mg, 44.5%). ¹H NMR (DMSO-d₆, ppm): 10.72 (s, 1H), 9.59 (bs,1H), 8.37 (d, 2H), 8.27 (bs, 1H), 7.90 (d, 2H), 7.60 (t, 4H), 7.43 (t,2H), 7.31 (m, 4H), 7.18 (m, 2H), 5.03 (s, 1H), 4.43 (d, 2H).

EXAMPLE 24-Chloro-N-(4-(N′-cyano-N″-quinolin-5-yl-guanidinomethyl)-phenyl)-benzenesulfonamide(SBR-11-3210) was synthesized as follows

N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (50 mg, 0.16mmol) and 4-chloro-benzenesulfonyl chloride (41 mg, 0.19 mmol) wereadded to pyridine (1 mL). An exothermic reaction occurred and thesuspension became homogeneous. This solution was shaken at roomtemperature for 12 hours. The reaction mixture was then diluted withethyl acetate (8 mL) and washed with water (5 mL×3). The organic phasewas dried over anhydrous sodium sulfate. The solvent was removed invacuo and the residue was triturated with diethyl ether to give a solidproduct in 76% yield. ¹H NMR (DMSO-d₆, ppm): 10.37 (s, 1H), 9.39 (s,1H), 8.96 (m, 1H), 8.12 (m, 1H), 8.02 (d, 1H), 7.69 (m, 3H), 7.63 (d,2H), 7.49 (m, 2H), 7.39 (m, 1H), 7.08 (m, 4H), 4.21 (d, 2H).

EXAMPLE 3 5-Dimethylamino-naphthalene-1-sulfonic acid(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-amide(SBR-11-2897) was synthesized as follows

N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (400 mg, 1.50mmol) and dansyl chloride (405 mg, 1.50 mmol) were combined in pyridine(15 mL). An exothermic reaction occurred and the suspension becamehomogeneous. This solution was shaken at room temperature for 12 hours.The reaction mixture was then diluted with ethyl acetate (80 mL) andwashed with water (40 mL×3). The organic phase was dried over anhydroussodium sulfate. The solvent was removed in vacuo to give a solid productwhich was purified by HPLC (yield=60%). ¹H NMR (DMSO-d₆, ppm): 10.73 (s,1H), 9.09 (bs, 1H), 8.57 (d, 2H), 8.44 (d, 2H), 8.36 (d, 1H), 8.21 (d,1H), 7.61 (m, 3H), 7.50 (s, 2H), 7.27 (d, 1H), 7.17 (d, 2H), 7.03 (d,2H), 4.38 (d, 2H).

EXAMPLE 41-(4-Ethoxy-phenyl)-3-[4-(N′-cyano-N″-pyridin4-yl-guanidinomethyl)-phenyl]-urea(SBR-11-3831) was synthesized as follows

N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (100 mg, 0.380mmol) and 1-ethoxy-4-isocyanato-benzene (61 mg,, 0.39 mmol) weredissolved in and mixture of N,N-dimethylformamide (2.0 mL).andtetrahydrofuran (1.0 mL). Triethylamine (0.060 mL, 0.390 mmol) wasadded. The reaction mixture was shaken at room temperature for 12 hours.The solvent was removed in vacuo to give the title compound (yield=85%).¹H NMR (DMSO-d₆, ppm): 8.34 (br, s, 2H); 7.41-7.21 (m, 10H); 6.82-6.76(m, 2H); 4.43 (s, 2H); 3.93 (dq, 2H); 1.28 (dt, 3H).

EXAMPLE 5

N-(4-Benzylamino-benzyl)-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-3536) was synthesized as follows

N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (146 mg, 0.55mmol), benzaldehyde (51 μl, 0.50 mmol), and sodium triacetoxyborohydride(159 mg, 0.750 mmol) were suspended in tetrahydrofuran (5.0 mL) andglacial acetic acid (0.2 mL) was added. The milky reaction mixture wasstirred at room temperature for 18 hours and then quenched by additionof a saturated aqueous solution of sodium bicarbonate (5 mL). Thissolution was extracted with ethyl acetate (40 mL) and the organic layerwas washed with 5% aqueous sodium bicarbonate (20 mL×2) and dried overanhydrous sodium sulfate. The solvent was removed in vacuo to give thecrude product which was purified by flash chromatography (SiO₂, 10%methanol in chloroform). The pure product was obtained in 67% yield. ¹HNMR (DMSO-d₆, ppm): 9.20 (bs, 1H), 8.34 (d, 2H), 8.12 (t, 1H), 7.10-7.38(m, 7H), 7.02 (d, 2H), 6.54 (d, 2H), 6.25 (t, 1H), 4.26 (m, 4H).

EXAMPLE 6N-(5-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-pentyl)-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-3776) was synthesized as follows

In a reaction flask under nitrogen with magnetic stirring2-(5-hydroxy-pentyl)-isoindole-1,3-dione (2.3 g, 10 mmol) was dissolvedin 50 mL of methylene chloride. For synthesis of2-(5-hydroxy-pentyl)-isoindole-1,3-dione, see Payne and Boger, Synth.Commun. 15, 1277-1290 (1985). Suberyl chloride (2.3 g, 10 mmol) wasadded followed by triethylamine (5 mL, 36 mmol) and the mixture wasstirred at room temperature for 18 hours. The solvent was removed invacuo and the residue was suspended in 150 mL of diethyl ether. Thesolid was removed by vacuum filtration and washed with 80 mL of diethylether. The filtrate and washings were combined and 50 mL of methanol wasadded to initiate precipitation. After chilling in an ice bath for 30minutes a white crystalline product was collected by vacuum filtration.The solid was dissolved in 50 mL of ethanol and hydrazine hydrate (10mL, 500 mmol) was added. The mixture was heated at reflux for 6 hoursand then allowed to cool to room temperature. The solvent was removed invacuo and the residue was treated with 20 mL of a 10% aqueous sodiumhydroxide solution. The alkaline solution was extracted with three 50 mLportions of diethyl ether and the combined organics were dried oversodium sulfate. The solvent was evaporated to give5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-pentylamine as aclear oil in quantitative yield.

1-Cyano-2-methyl-3-pyridin-4-yl-isothiourea (573 mg, 3.00 mmol) and5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-pentylamine (886mg, 3.00 mmol) were dissolved in pyridine (20 mL). Triethylamine (2 mL,14 mmol) was added followed by (4-dimethylamino)pyridine (5.0 mg, 0.04mmol). The reaction mixture was stirred at 86□ C. for 12 hours. Aftercooling to room temperature, the reaction mixture was diluted withdiethyl ether (50 mL). The resulting precipitate was collected byfiltration and washed with diethyl ether. The crude product wasrecrystalized from methanol and diethyl ether to give the desiredproduct as a white crystalline solid (yield 85%). ¹H NMR (CDCl₃, ppm):8.54 (dd, 2H), 7.41-7.12 (m, 10H), 5.29 (s, 1H), 3.56-3.41 (m, 4H), 3.32(dd, 2H), 3.05-2.95 (m, 2H), 1.71-1.41 (m, 6H).

EXAMPLE 7N-Cyano-N′-[2-(4-naphthalen-1-ylmethyl-piperazin-1-yl)-ethyl]-N″-pyridin-4-yl-guanidine(SBR-11-4326) was synthesized as follows

S-methyl-N-cyano-N′-pyridylisothiourea (3.84 g, 20 mmol) and1-(2-aminoethyl)piperazine (2.89 ml, 22 mmol) were suspended in pyridine(8 mL) in a reaction flask equipped with magnetic stirring undernitrogen. Triethylamine (2.8 mL, 20 mmol) was added followed by(4-dimethylamino)-pyridine (cat., 100 mg). The reaction mixture becameclear. It was stirred at 50-60° C. for 12 hours and cooled to roomtemperature. Ether (100 mL) was then added and precipitate formed. Theprecipitate was collected to give crudeN-cyano-N′-(2-piperazin-1-yl-ethyl)-N″-pyridin-4-yl-guanidine which wasused without further purification. ESMS 274.2 (M+1).

N-cyano-N′-(2-piperazin-1-yl-ethyl)-N″-pyridin-4-yl-guanidine (207 mg,0.757 mmol) and 1-nathphylaldehyde (118 mg, 0.757 mmol) were suspendedin a tetrahydrofuran (5 ml). Sodium triacetoxyborohydride (241 mg, 1.14mmol) was added followed by glacial acetic acid (cat. 5 drops). Thereaction mixture was stirred at room temperature for 12 hours and thenquenched with saturated sodium bicarbonate (5 mL). The final product wasextracted with 100 mL ethyl acetate. The organic layer was washed with5% sodium bicarbonate (2×20 mL), then dried over anhydrous sodiumsulfate. The solvent was removed in vacuo to give the crude productwhich was further purified by flash column chromatography (SiO₂, 10%MeOH in EtOAc). The pure title product was obtained in 35% yield in twosteps. ¹H-NMR ((CD₃OD, ppm): 8.38 (d, 2H), 8.26 (d, 1H), 7.81-7.86 (m,3H), 7.40-7.50(m, 5H), 3.95 (s, 2H), 3.48 (t, 2H), 2.58 (m, 10H). ESMS414.4 (M+1), 436.3 (M+23).

EXAMPLE 8N-[2-(4-Benzhydryl-piperazin-1-yl)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4408) was synthesized as follows

N-cyano-N′-(2-piperazin-1-yl-ethyl)-N″-pyridin-4-yl-guanidine (273 mg, 1mmol) (prepared using the procedure described in Example 7) andbromodiphenylmethane (247 mg, 1 mmol) was dissolved in dimethylformamide(1.5 mL), followed by the addition of triethylamine (0.21 mL, 1.5 mmol).The reaction solution was stirred at room temperature under nitrogen for10-15 hours and then diluted with 100 mL ethyl acetate. The organiclayer was washed with water (3×30 mL) and dried over anhydrous sodiumsulfate. The solvent was removed in vacuo to give crude title product.The final product was further purified by flash column chromatography(SiO₂, 10% MeOH in EtOAc). The pure product was obtained in 50% yield intwo steps. ¹H-NMR (CD₃OD, ppm): 8.36 (d, 2H), 7.18-7.43 (m, 12H), 4.29(s, 1H), 3.46 (t, 2H), 2.45-2.61 (m, 10H). ESMS 440.4 (M+1), 462.4(M+23).

EXAMPLE 9N-[2-(4-Benzhydryloxy-piperidin-1-yl)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-114483) was synthesized as follows

To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.),4-hydroxypiperidine (1.01 g, 10 mmol, 1.0 eq.), and p-toluenesulfonicacid monohydrate (2.09 g, 1.1 eq.) were suspended in toluene (400 ml).The mixture was refluxed with a Dean-Stark condenser for 3-4 hours.After cooling to room temperature, the solution was washed with 5% NaOHsolution (2×20 ml), then with water (2×20 ml). The solution was thendried over anhydrous Na₂SO₄. The solvent was then removed under vacuum.The crude product, 4-benzhydryloxy-piperidine was obtained (2.46 g,92.0% yield). ¹H-NMR (CDCl₃, ppm): 7.10-7.25 (m, 10H), 5.41 (s, 1H),3.48 (m, 1H), 3.13 (m, 2H), 2.78 (m, 2), 1.86 (m, 2H), 1.66 (m, 2H).ESMS 268.1 (M+1), 290.1 (M+23).

The mixture of 4-benzhydryloxy-piperidine (1.85 g, 3.4 mmol, 1.0 eq.),N-(2-bromoethyl)phthalimide (0.855 g, 3.4 mmol, 1.0 eq.), K₂CO₃ (0.705g, 5.1 mmol, 1.5 eq.), and NaI (0.713 g, 4.8 mmol, 1.4 eq.) in2-butanone (20 ml) was refluxed for 2-3 hours. The mixture was thencooled to room temperature. The white solid was filtered off and waswashed with small amount of CHCl₃. The filtrates were combined andconcentrated. The resulted residue was dissolved in CHCl₃ (100 ml). Thesolution was washed with water (3×10 ml), then dried over anhydrousNa₂SO₄. After removed all solvent, the crude product,2-[2-(4-benzhydryloxy-piperidin-1-yl)-ethyl]-isoindole-1,3-dione wasyielded (1.5 g, 100% yield). ¹H-NMR (CDCl₃, ppm): 7.84 (m, 2H), 7.70 (m,2H), 7.20-7.40 (m, 10H), 5.50 (s, 1H), 3.80 (t, 2H), 3.39 (m, 1H), 2.82(m, 2H), 2.59 (t, 2H), 2.18 (m, 2H), 1.83 (m, 2H) 1.67 (m, 2H). ESMS441.2 (M+1), 463.2 (M+23).

2-[2-(4-benzhydryloxy-piperidin-1-yl)-ethyl]-isoindole-1,3-dione (0.548g, 1.24 mmol) was dissolved in ethanol (2 ml), followed by the additionof hydrazine hydrate (large excess, 2-3 ml). The solution was refluxedfor 2 hours. The white solid was precipitated. After cooling to the roomtemperature, the white solid was filtered off and washed with smallamount of ethanol. The filtrates were combined and concentrated. Theresulted residue was dissolved in toluene (100 ml). The solution waswashed with water (3×20 ml) and dried over anhydrous Na₂SO₄. Afterevaporated the solvent, the crude product,2-(4-benzhydryloxy-piperidin-1-yl)-ethylamine was obtained (0.326 g,84.4% yield). ¹H-NMR (CD₃OD, ppm): 7.15-7.40 (m, 10H), 5.58 (s, 1H),3.46 (m, 1H), 2.77 (m, 2H), 2.72 (t, 2H), 2.40 (t, 2H), 2.18 (m, 2H),1.89 (m, 2H), 1.70 (m, 2H). ESMS 311.2 (M+1), 333.2 (M+23).

The solution of 2-(4-benzhydryloxy-piperidin-1-yl)-ethylamine (310 mg, 1mmol) and S-methyl-N-cyano-N′-pyridylisothiourea (192 mg, 1 mmol) inisopropanol (2 ml) was stirred at room temperature overnight. The whitesolid was precipitated. The solid was collected and washed with smallamount isopropanol and then with ether. The title compound was obtained(180 mg, 38.4% yield). ¹H-NMR (CD₃OD, ppm): 8.38 (d, 2H), 7.41 (d, 2H),7.20-7.40 (m, 10H), 5.60 (s, 1H), 3.52 (m, 1H), 3.48 (t, 2H), 2.88 (m,2H), 2.61 (t, 2H), 2.34 (m, 2H), 1.92 (m, 2H), 1.76 (m 2H). ESMS 455.3(M+1), 477.3 (M+23).

EXAMPLE 10N-[2-(4-Benzhydryloxymethyl-piperidin-1-yl)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-114540) was synthesized as follows

To the suspension of LiAlH₄ in THF (250 ml) at 0° C., the solution ofethyl isonipecotate (5.0 g, 32 mmol) in THF (100 ml) was added in drops.After the addition, the solution was stirred at room temperatureovernight. The reaction flask was cooled in ice bath. Saturated Na₂SO₄was added until no more gas released. The reaction was then filteredthrough a bed of celite to obtain clear solution. The solvent wasremoved under vacuum. The waxy solid piperidin-4-yl-methanol wasobtained (3.1 g, 83% yield). The crude product will be used withoutfurther purification. ESMS 115.9 (M+1).

To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.),piperidin-4-yl-methanol (1.15 g, 10 mmol, 1.0 eq.), andp-toluenesulfonic acid monohydrate (2.09 g, 1.1 eq.) were suspended intoluene (400 ml). The mixture was refluxed with a Dean-Stark condenserfor 3-4 hours. After cooling to room temperature, the solution waswashed with 5% NaOH solution (2×20 ml), then with water (2×20 ml). Thesolution was then dried over anhydrous Na₂SO₄. The solvent was thenremoved under vacuum. The crude product4-(1,1-diphenyl-methoxymethyl)-piperidine was obtained (2.33 g, 82.8%yield). ESMS 268.1 (M+1), 290.1 (M+23).

The mixture of 4-(1,1-diphenyl-methoxymethyl)-piperidine (0.760 g, 2.7mmol, 1.0 eq.), N-(2-bromoethyl)phthalimide (0.686 g, 2.7 mmol, 1.0eq.), K₂CO₃ (0.560 g, 4.1 mmol, 1.5 eq.), and NaI (0.567 g, 3.8 mmol,1.4 eq.) in 2-butanone (10 ml) was refluxed for 2-3 hours. The mixturewas then cooled to room temperature. The white solid was filtered offand was washed with small amount of CHCl₃. The filtrates were combinedand concentrated. The resulted residue was dissolved in CHCl₃ (80 ml).The solution was washed with water (3×10 ml), then dried over anhydrousNa₂SO₄. After removed all solvent, the crude product2-{2-[4-(1,1-diphenyl-methoxymethyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dionewas yielded (0.980 g, 79.8% yield).

2-{2-[4-(1,1-Diphenyl-methoxymethyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione(0.95 g, 2.1 mmol) was dissolved in ethanol (5 ml), followed by theaddition of hydrazine hydrate (large excess, 2-3 ml). The solution wasstirred at room temperature overnight. The white solid was precipitated.The white solid was filtered off and washed with small amount ofethanol. The filtrates were combined and concentrated. The resultedresidue was dissolved in toluene (100 ml). The solution was washed withwater (3×20 ml) and dried over anhydrous Na₂SO₄. After evaporated thesolvent, the crude product2-[4-(1,1-diphenyl-methoxymethyl)-piperidin-1-yl]-ethylamine wasobtained (0.335 g, 49.4% yield).

The solution of2-[4-(1,1-diphenyl-methoxymethyl)-piperidin-1-yl]-ethylamine (320 mg,0.99 mmol) and S-methyl-N-cyano-N′-pyridylisothiourea (190 mg, 0.99mmol) in isopropanol (2 ml) was stirred at room temperature overnight.The white solid was precipitated. 50 ml Ether was added and the mixturewas stirred for 0.5 hr. The solid was collected and washed with smallamount isopropanol and then with ether. The title compound was obtained(398 mg, 89.8% yield). ¹H-NMR (CD₃OD, ppm): 8.24 (d, 2H), 7.20-7.45 (m,12H), 5.37 (s, 1H), 3.48 (t, 2H), 3.34 (d, 2H), 3.05 (d, 2H), 2.14 (m,2H), 1.81 (d, 2H), 1.72 (m, 1H), 1.45 (m, 2H). ESMS 469.3 (M+1), 491.2(M+23).

EXAMPLE 11

N-{2-[4-(Benzhydryl-amino)-piperidin-1-yl]-ethyl}-N′-cyano-N″-pyridin4-yl-guanidine(SBR-11-4583) was synthesized as follows

The mixture of 4-oxo-piperidine-1-carboxylic acid benzyl ester (0.98 ml,5 mmol, 1.0 eq), aminodiphenylmethane (1.30 mL, 7.5 mmol, 1.5 eq), andNaBH₃(OAc)₃ was suspended in THF (10 mL). AcOH (10 drops as cat.) wasadded. The mixture was stirred at room temperature overnight. NaHCO₃(saturated, 5 mL) was then added. The organic product was extracted withEtOAc (100 mL). The EtOAc layer was washed with H20 (3×20 mL), driedover anhydrous Na₂SO₄. The solvent was removed and the crude product4-Oxo-piperidine-1-carboxylic acid benzyl ester was obtained (2.79 g).The crude product was used without further purification.

The 4-oxo-piperidine-1-carboxylic acid benzyl ester (crude, 2.7 g) wasdissolved in HOAc, followed by the addition of the solution of HBr inHOAc (30%). (1.4 mL, 1.05 eq). The solution was stirred at roomtemperature overnight. The solid was precipitated. About 50 mL ether wasadded and the mixture was stirred for a while. The solid was collectedand washed with ether. The crude product benzhydryl-piperidin-4-yl-aminehydrogen bromide salt was yielded (2.7 g).

The mixture of benzhydryl-piperidin-4-yl-amine hydrogen bromide salt(1.74 g, 5 mmol, 1.0 eq.), N-(2-bromoethyl)phthalimide (1.27 g, 5 mmol,1.0 eq.), K₂CO₃ (1.73 g, 12.5 mmol, 2.5 eq.), and NaI (1.05 g, 7.0 mmol,1.4 eq.) in 2-butanone (20 ml) was refluxed for 2-3 hours. The mixturewas then cooled to room temperature. The white solid was filtered offand was washed with small amount of CHCl₃. The filtrates were combinedand concentrated. The resulted residue was dissolved in CHCl₃ (100 ml).The solution was washed with water (3×20 ml), then dried over anhydrousNa₂SO₄. After removed all solvent, the crude product2-{2-[4-(benzhydryl-amino)-piperidin-1-yl]-ethyl} -isoindole-1,3-dionewas yielded (2.70 g).

The crude2-{2-[4-(benzhydryl-amino)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione(2.70 g) was dissolved in ethanol (5 ml), followed by the addition ofhydrazine hydrate (large excess, 2-3 ml). The solution was stirred atroom temperature overnight. The white solid was precipitated. The whitesolid was filtered off and washed with small amount of ethanol. Thefiltrates were combined and concentrated. The resulted residue wasdissolved in toluene (100 ml). The solution was washed with water (3×15ml) and dried over anhydrous Na₂SO₄. After evaporated the solvent, thecrude product [1-(2-amino-ethyl)-piperidin-4-yl]-benzhydryl-amine wasobtained (0.150 g, 7.9% yield).

The solution of [1-(2-amino-ethyl)-piperidin-4-yl]-benzhydryl-amine (150mg, 0.485 mmol) and S-methyl-N-cyano-N′-pyridylisothiourea (93 mg, 0.485mmol) in isopropanol (2 ml) was stirred at room temperature overnight.All the solvent was removed. The final product was purified by column(10% methanol in EtOAc). The title compound was obtained (74 mg, 33.6%yield). ¹H-NMR (CD₃OD, ppm): 8.38 (d, 2H), 7.15-7.50 (m, 12H), 5.05 (s,1H), 3.46 (t, 2H), 2.98 (d, 2H), 2.57 (t, 2H), 2.48 (m, 1H), 2.04 (m,4H), 1.54 (m, 2H), ESMS 454.2 (M+1), 476.3 (M+23).

EXAMPLE 12N-[3-(4-Benzhydryl-piperazin-1-yl)-propyl]-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4629) was synthesized as follows

The mixture of 1-(diphenylmethyl)piperazine (505 mg, 2 mmol, 1.0 eq.),N-(2-bromoethyl)phthalimide (508 mg, 2 mmol, 1.0 eq.), K₂CO₃ (415 g, 3mmol, 1.5 eq.), and NaI (420 g, 2.8 mmol, 1.4 eq.) in 2-butanone (10 ml)was refluxed for 2-3 hours. The mixture was then cooled to roomtemperature. The white solid was filtered off and was washed with smallamount of CHCl₃. The filtrates were combined and concentrated. Theresulted residue was dissolved in CHCl₃ (100 ml). The solution waswashed with water (3×10 ml), then dried over anhydrous Na₂SO₄. Afterremoved all solvent, the crude product2-[3-(4-benzhydryl-piperazin-1-yl)-propyl]-isoindole-1,3-dione wasyielded (935 mg, 110% yield).

The crude 2-[3-(4-benzhydryl-piperazin-1-yl)-propyl]-isoindole-1,3-dione(930 mg) was dissolved in ethanol (2 ml), followed by the addition ofhydrazine hydrate (large excess, 2-3 ml). The solution was stirred atroom temperature overnight. The white solid was precipitated. The whitesolid was filtered off and washed with small amount of ethanol. Thefiltrates were combined and concentrated. The resulted residue wasdissolved in toluene (100 ml). The solution was washed with water (3×15ml) and dried over anhydrous Na₂SO₄. After evaporated the solvent, thecrude product 3-(4-benzhydryl-piperazin-1-yl)-propylamine was obtained(276 mg, 42.7% yield).

The solution of 3-(4-benzhydryl-piperazin-1-yl)-propylamine (275 mg,0.834 mmol) and S-methyl-N-cyano-N′-pyridylisothiourea (160 mg, 0.834mmol) in isopropanol (2 ml) was stirred at room temperature overnight.The white solid was precipitated. 50 ml Ether was added and the mixturewas stirred for 0.5 hr. The solid was collected and washed with smallamount isopropanol and then with ether. The title compound was obtained(235 mg, 59.5% yield). ¹H-NMR (CD₃OD, ppm): 8.38 (d, 2H), 7.10-7.45 (m,12H), 4.19 (s, 1H) 3.42 (t, 2H), 2.46 (m. 10H), 1.79 (m, 2H) ESMS454.2(M+1), 476.2 (M+23).

EXAMPLE 13N-[2-(4-Benzhydrylsulfanyl-piperidin-1-yl)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4630) was synthesized as follows

H₂S gas bubbled through 1-methyl-4-piperidine (30 g, 0.265 mol) inisopropanol (75 mL) maintained at ice bath. After an hour, the mixturewas filtered to give 6.5 g of the gem-dithiol. The filtrate was treatedwith H₂S gas for another 2 hrs to give another 8.9 g. The filtrate wascontinuously treated with H₂S gas for 2-3 hrs at the ice bath. The H₂Sgas was removed and the mixture was stirred at room temperatureovernight. Filtration gave a further 7.5 g of gem-dithiol. The totalyield is 22.9 g. The gem-dithiol was dried in the dark overnight. Thegem-dithiol (10 g, 55.2 mmol) was added in small portions to as stirredsuspension of NaBH₄ (2.5 g, 65.9 mmol) in isopropanol (25 mL) maintainedat ice bath. After the addition, the mixture was stirred for 0.5 hr atthe ice bath, then at room temperature overnight. The mixture wasrefluxed for 2 hours, cooled, and concentrated. The resulted residue wasdiluted with water and ether. The ether layer was separated and theaqueous layer was extracted with ether. Both ether fractions werecombined and washed with brine and dried over Na₂SO₄. The solvent wasremoved and the final product 1-methyl-4-mercaptopiperidine was obtainedfrom distillation under pressure (5.2 g).

The mixture of 1-methyl-mercaptopiperidine (0.350 g, 2.67 mmol, 1.1eq.), bromodiphenylmethane (0.599 g, 2.42 mmol, 1.0 eq.), and K₂CO₃(0.502 g, 3.63 mmol, 1.5 eq.) was suspended in acetone and heated at40-50° C. for 3 days. Then, the mixture was refluxed for 12 hrs. Themixture was cooled to room temperature and the solid was filtered off.The solid was washed with small amount of acetone. The filtrates werecombined and the solvent was removed to afford the product4-benzhydrylsulfanyl-1-methyl-piperidine (0.353 g, 49.0%).

The solution of 4-benzhydrylsulfanyl-1-methyl-piperidine (350 mg, 1.18mmol) and ethyl chloroformate (0.33 mL, 3.54 mmol, 3 eq.) in toluene (15ml) was refluxed for 5 hrs. The solution was cooled to room temperatureand then washed with diluted HCl (2.0 N, 2×5 mL). The solution was driedover anhydrous Na₂SO₄. The solvent was moved and the crude product4-benzhydrylsulfanyl-piperidine-1-carboxylic acid ethyl ester wasyielded (322 mg, 76.8% yield).

The solution of 4bezhydrylsulfanyl-piperidine-1-carboxylic acid ethylester (320 mg, 0.9 mmol) and 40% NaOH (prepared from 216 mg NaOH and0.33 ml H₂0) in EtOH (10 mL) was refluxed overnight. After the removalof the solvent, the resulted residue was diluted with water andextracted with ether. The ether layer was washed with diluted HCl (0.2N). The aqueous fractions were combined and made alkaline with K₂CO₃ andthen extracted with EtOAc. The EtOAc layer was washed with water, driedover Na2SO4 and evaporated to afford 4-bnzhydrylsulfanyl-piperidine asoil (12 mg, 4.7%).

The mixture of 4-benzhydrylsulfanyl-piperidine (12 mg, 0.0423 mmol, 1.0eq.), N-(2-bromoethyl)phthalimide (11 mg, 0.0423 mmol, 1.0 eq.), K₂CO₃(9 mg, 0.0635 mmol, 1.5 eq.), and NaI (9 mg, 0.0600 mmol, 1.4 eq.) in2-butanone (5 ml) was refluxed for 2-3 hours. The mixture was thencooled to room temperature. The solvent was removed and the resultedresidue was dissolved in CHCl₃ (25 ml). The solution was washed withwater (3×5 ml), then dried over anhydrous Na₂SO₄. After removed allsolvent, the crude product2-[2-(4-benzhydrylsulfanyl-piperidin-1-yl)-ethyl]-isoindole-1,3-dionewas yielded (15 mg).

The crude2-[2-(4-benzhydrylsulfanyl-piperidin-1-yl)-ethyl]-isoindole-1,3-dione(930 mg) was dissolved in ethanol (0.5 ml), followed by the addition ofhydrazine hydrate (large excess, 1 ml). The solution was stirred at roomtemperature overnight. The white solid was precipitated. The mixture wasdiluted with 50 ml toluene and the toluene layer was washed with waswashed with water (3×5 ml) and dried over anhydrous Na₂SO₄. Afterevaporated the solvent, the crude2-(4-benzhydrylsulfanyl-piperidin-1-yl)-ethylamine was obtained (10 mg).

The solution of 2-(4-benzhydrylsulfanyl-piperidin-1-yl)-ethylamine (10mg, 0.0306 mmol) and S-methyl-N-cyano-N′-pyridylisothiourea (6 mg,0.0306 mmol) in isopropanol (1 mL) was stirred at room temperatureovernight. All the solvent was removed and the final product waspurified by pre-HPLC (AcCN/methanol with 0.05% TFA). The title compoundwas obtained (3 mg 20.8% yield). ¹H-NMR (CD₃OD, ppm): 8.56 (d, 2H), 7.68(d, 2H), 7.20-7.50 (m, 10H), 5.38 (s, 1H), 3.85 (t, 2H), 3.68 (m, 1H),2.95 (m, 2H), 2.66 (m, 2H), 2.19 (m, 2H), 1.85 (m, 2H). ESMS 471.2(M+1), 493.2 (M+23).

EXAMPLE 14N-{2-[2-(2-Chloro-phenoxy)-ethoxy]-ethyl}-N′-cyano-″-pyridin-4-yl-guanidine( SBR-11-4435) was synthesized as follows

To a reaction flask, 2-(2-aminoethoxy)ethanol (5.78 g, 55 mmol) andS-methyl-N-cyano-N′-pyridylisothiourea (9.60 g, 50 mmol) were suspendedin pyridine (40 mL). Triethylamine (7 mL, 50 mmol) was added followed by(4-dimethylamino)pyridine (cat., 100 mg). The reaction mixture becameclear solution, which was stirred at 50-60° C. for 10 hours. Thereaction mixture was then cooled to room temperature. Ether (200 mL) wasadded and the resulting solid was collected to giveN-[2-(2-hydroxyethoxy)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine (12.0g, 48 mmol, 96%) as a white solid which was used without furtherpurification.

N-[2-(2-hydroxyethoxy)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine (0.50g, 2.00 mmol) was dissolved in N-methylpiperidine (5 mL) with gentleheating. Tetrahydrofuran (5 mL) and triphenylphosphine (0.629 g, 2.40mmol) were added and the mixture was cooled to 0° C. Diethylazodicarboxylate (0.42 g, 2.40 mmol) was added dropwise. The mixture wasstirred at room temperature overnight. The solvents was then removed invacuo. The final product was further purified by flash columnchromatography (10% MeOH in ethyl acetate). The title product was givenas a light brown viscous oil (0.40 g, 56% yield). ¹H NMR (CDCl₃, ppm):8.19 (br s, 2H), 6.88-7.70 (m, 8H), 4.23 (t, 2H), 4.00 (t, 2H), 3.86 (t,2H), 3.69 (t, 2H). MS: 359.11 (calc'd); 360.2 (M+1); 382.2 (M+23).

EXAMPLE 15N-{2-12-(4-Chloro-phenoxy)-ethoxy]-ethyl}-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4433) was synthesized as follows

2-(2-Aminoethoxy)ethanol (5.26 g, 50 mmol) and sodium hydroxide (2.1 g,52.5 mmol) were dissolved in water (200 mL). The resulted solution wascooled in ice bath, followed by the dropwise addition of benzylchloroformate. After the addition, the reaction mixture was continuouslystirred in ice bath for another hour. The desired product was extractedwith ethyl acetate (EtOAc, 200 mL). The EtOAc layer was washed withwater (3×100 mL) and then dried over anhydrous sodium sulfate. Thesolvent was removed in vacuo to yield the crude product. The product wasfurther purified by flash column chromatography (SiO₂, 1:2 Hexane:EtOAc)to give [2-(2-hydroxy-ethoxy)-ethyl]-carbamic acid benzyl ester as aclear oil (8.07 g, 67.5% yield). ¹H-NMR (CDCl₃, ppm) 7.35 (m, 5H), 5.34(b, 1H), 5.10 (s, 2H), 3.71 (m, 2H), 3.56 (m, 4H), 3.41 (m, 2H), 2.20 (b1H),. ESMS 240.0 (M+1).

[2-(2-Hydroxy-ethoxy)-ethyl]-carbamic acid benzyl ester (2.39 g, 10mmol), 4-chlorophenol (1.29 g, 10 mmol), and triphenylphosphine (2.89 g,11 mmol) were dissolved in tetrahydrofuran (50 ml), followed by thedropwise addition of diethylazodicarboxylate (1.73 ml, 11 mmol). Afterthe addition, the reaction solution was stirred at room temperature for10-12 hours. The solvent was then removed in vacuo. The remainingresidue was stirred in 30% EtOAc in hexane (200 mL) for 10 minutes and awhite solid was formed. This solid was then filtered and washed with 30%EtOAc in hexane (3×20 mL). The filtrates were combined and the solventswere removed in vacuo. The remaining residue was purified by flashcolumn chromatography (SiO₂, 2:1 hexane:EtOAc) to give{2-[2-(4-chloro-phenoxy)-ethoxy]-ethyl}-carbamic acid benzyl ester asclear solid (3.49 g, 99.8% yield). ¹H-NMR (CDCl₃, ppm) 7.35 (m, 5H),7.20 (d, 2H), 6.82 (d, 2H), 5.22 (b, 1H), 5.10 (s, 2H), 4.07 (t, 2H),3.80 (t, 2H), 3.62 (t, 2H), 3.41 (q, 2H). ESMS 350.1 (M+l), 372.1(M+23).

{2-[2-(4-Chloro-phenoxy)-ethoxy]-ethyl}-carbamic acid benzyl ester (3.49g, 10 mmol) was suspended in 10 mL glacial acetic acid. A solution of 30wt % hydrogen bromide in glacial acetic acid was added and the reactionmixture was stirred at room temperature for 10 hours. Ether (100 mL) wasadded to precipitate 2-[2-(4-chloro-phenoxy)-ethoxy]-ethylaminehydrobromide salt as a white solid which was then collected and washedwith ether (3×10 mL) (1.55 g, 52.3% yield). ¹H-NMR (CD₃OD, ppm) 7.26 (d,2H), 6.93 (d, 2H), 4.15 (t, 2H), 3.88 (t, 2H), 3.78 (t, 2H), 3.15 (t,2H). ESMS 216.0 (M+1).

To a reaction flask, S-methyl-N-cyano-N′-pyridylisothiourea (0.577 g, 3mmol) and 2-[2-(4-chloro-phenoxy)ethoxy]ethylamine hydrobromide salt(0.979 g, 3.3 mmol) were suspended in pyridine (3 mL). Triethylamine(0.84 1L, 6 mmol) was added followed by (4-dimethylamino)-pyridine(cat., 50 mg). The reaction mixture became clear solution, which wasstirred at 50-60° C. for 12 hours. The reaction mixture was then cooledto room temperature. Ether (50 mL) was added to precipitate the desiredproduct, which was then purified by crystallization from MeOH/H₂O (0.86g, 79.7% yield). ¹H-NMR (CD₃OD, ppm): 8.33 (d, 2H), 7.33 (m, 6H), 7.20(m, 6H), 3.64 (t, 2H), 3.58 (m, 4H), 3.41 (t, 2H), ESMS 444.3 (M+1),466.3 (M+23).

EXAMPLE 16N-{2-[2-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yloxy)-ethoxy]-ethyl}-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4416) was synthesized as follows

To a solution of 2-(2-aminoethoxy)ethanol (10.51 g, 100 mmol, 1.00equiv) in 50 mL MeOH at 0° C. was slowly added ethyl trifluoroacetate(17.0 g, 120 mmol, 1.20 equiv). The mixture was stirred at roomtemperature for 5 hours. Solvents were then removed to yield2-(2-N-trifluoroacetyl-aminoethoxy)ethanol as viscous colorless oil(20.0 g, 100%).

2-(2-N-trifluoroacetyl-aminoethoxy)ethanol (5.0 g, 25 mmol, 1.00 equiv)and 5-chlorodibenzosuberane (5.72 g, 25 mmol, 1.00 equiv) were dissolvedin 50 1L CH₂Cl₂. Triethylamine (3.03 g, 30 mmol, 1.20 equiv) was addedto the solution at room temperature. The mixture was stirred at roomtemperature for 3 hours. The solvent was removed in vacuo. The resultedresidue was diluted with ethyl acetate (300 mL) The solvent was removedin vacuo to yield5-[2-(2-N-trifluoroacetylaminoethoxy)ethoxy]dibenzosuberane as viscouscolorless oil which was treated with 30 mL 2M NaOH in 60 mL MeOH at roomtemperature for 4 hours. Most of solvent was removed on rotaryevaporator. EtOAc/aqueous workup yielded5-[2-(2-aminoethoxy)ethoxy]-dibenzosuberane as a light yellow viscousoil. [M+H] calculated: 297.17, found: 298.2.

The crude product obtained above andS-methyl-N-cyano-N′-pyridylisothiourea (4.85 g, 25 mmol, 1.00 equiv)were dissolved in pyridine (40 mL), followed by the addition oftriethylamine (3.5 mL, 25 mmol, 1.00 equiv) and(4-dimethylamino)pyridine (cat., 100 mg). The reaction mixture wasstirred at 50-55° C. for 10 hours. Ether (100 mL) was added andprecipitate was formed, which was then collected and washed with ether(3×50 mL). The final product was purified by flash column chromatography(10% methanol in ethyl acetate) to yield the title product (10.0 g, 22.7mmol, 91%). ¹H-NMR (CDCl₃, ppm): 8.22 (d, 2H), 7.09-7.28 (m, 12H), 5.29(s, 1H), 3.74-3.77 (m, 2H), 3.62-3.68 (m, 4H), 3.46-3.55 (m, 4H),2.87-2.95 (m, 2H). ESMS 442.4 (M+1), 462.4 (M+23).

EXAMPLE 17N-{2-[2-(4-Methoxy-phenyl-sulfanyl)-ethoxyl-ethyl}-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4443) was synthesized as follows

To a solution of 2-(2-aminoethoxy)ethanol (11.56 g, 110 mmol, 1.10equiv) in 200 mL THF and 50 mL NaHCO₃ (saturated) at 0° C. was slowlyadded di-tert-butyl-dicarbonate (21.83 g, 100 mmol, 1.00 equiv). Themixture was stirred at room temperature for 5 hours. The solvent wasremoved in vacuo. The remaining residue was diluted with ethyl acetate(300 mL). The organic phase was washed with H₂O (3×100 mL) and driedover anhydrous sodium sulfate. The solvent was evaporated to yield2-(2-N-Boc-aminoethoxy)ethanol as a viscous colorless oil (20.5 g,100%).

2-(2-N-Boc-aminoethoxy)ethanol (12.38 g, 60.4 mmol, 1.00 equiv) andtriethylamine (7.50 g, 72.5 mmol, 1.20 equiv) were dissolved in 100 mLCH₂Cl₂ at 0° C. Methanesulfonyl chloride (8.30 g, 72.50 mmol, 1.20equiv) was slowly added to the solution. The mixture was stirred at roomtemperature for 3 hours. The reaction solution was washed with H₂O (3×30mL) and dried over anhydrous sodium sulfate. The solvent was removed invacuo to yield 2-(2-N-Boc-aminoethoxy)ethyl methanesulfonate as aviscous colorless oil.

2-(2-N-Boc-aminoethoxy)ethyl methanesulfonate (1.486 g, 5.25 mmol, 1.05equiv) and 4-methoxybenzenethiol (0.71 g, 5.0 mmol, 1.0 equiv) weredissolved in 20 mL THF. 5 mL 2 M NaOH solution was added, followed by1.0 g of Aliquat 336. The mixture was stirred at room temperature for 14hours. The solution was concentrated to yield a light yellow viscous oilwhich was then treated with 2 mL TFA in 10 mL methylene chloride at roomtemperature for 2 hours. The solvent was removed on rotary evaporator.The residue was neutralized with excess 2 M NaOH solution. The productwas extracted with ethyl acetate (150 mL). The ethyl acetate layer waswashed with H₂O (3×30 mL) and dried over anhydrous sodium sulfate. Thesolution was concentrated in vacuo to yield 2-(2′-aminoethoxy)ethyl4-methoxyphenyl sulfide as a light yellow viscous oil (crude). [M+H]calculated: 227.10, found: 228.0.

2-(2′-Aminoethoxy)ethyl 4methoxyphenyl sulfide obtained in the proceduredescribed above and S-methyl-N-cyano-N′-pyridylisothiourea (0.768 g, 4.0mmol, 0.80 equiv) were dissolved in pyridine (4 ml), followed by theaddition of triethylamine (0.56 mL, 4.0 mmol, 1.00 equiv) and(4-dimethylamino)pyridine (cat., 50 mg). The reaction mixture wasstirred at 50-55° C. for 10 hours. The reaction solution was thensolidified by ether (50 mL). The solid was collected and washed withether (3×10 mL). The final product was purified by flash columnchromatography (10% MeOH in ethyl acetate) to yield the title product asviscous light yellow oil (1.43 g, 3.85 mmol, 96%). ¹H-NMR (CDCl₃, ppm):8.44 (d, 2H), 7.53 (d, 2H), 7.33 (d, 2H), 711 (br s, 2H), 6.84 (d, 2H),3.80 (s, 3H), 3.62-3.75 (m, 6H), 3.06 (t, 2H). ESMS 372.1 (M+l), 394.2(M+23).

EXAMPLE 18N-[2-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yloxy)-ethyl]-N-[2-(N′-cyano-N″-pyridin-4-yl-guanidino)-ethyl]-acetamide(SBR-11-4427) was synthesized as follows

To a solution of 2-(2-aminoethylamino)ethanol (1.15 g, 11 mmol, 1.10equiv) in 50 mL MeOH at 0° C. was slowly added ethyl trifluoroacetate(1.42 g, 10 mmol, 1.00 equiv). The mixture was stirred at roomtemperature for 5 hours. Solvents were then removed, and the residue wasdissolved in 50 mL methylene chloride. Triethylamine (1.52 g, 15 mmol)was added followed by acetyl chloride (0.94 g, 12 mmol, 1.20 equiv).Removal of solvent yieldedN-acetyl-N-(2-trifluoroacetylaminoethyl)-(2′-hydroxyethyl)amine (crude)as a white solid. This crude product was subjected to a series ofreactions similar to those for SBR-11-4416. 0.60 g final product wasisolated as a white solid after HPLC purification. ¹H NMR (CDCl₃, ppm):8.47(d, 2H), 7.99 (brs, 2H), 7.14-7.35 (m, 10H), 5.20 (s, 1H), 2.96-3.56(m, 12H), 2.18 (s, 3H). MS: 482.24 (calc'd); 483.5 (M+1).

EXAMPLE 19N-(3-{Methyl-13-(N′-cyano-N″-pyridin-4-yl-guanidino)propyl]-amino}-propyl)-2,2-diphenyl-acetamide(SBR-11-4491) was synthesized as follows

To a solution of 3,3′-diamino-N-methyldipropylamine (3.05 g, 21.0 mmol,7.0 equiv.) in 10 mL pyridine at room temperature was added slowlydiphenylacetyl chloride (0.692 g, 3.0 mmol, 1.0 equiv.). The reactionmixture was stirred at room temperature overnight, diluted with 100 mLEtOAc, and washed with 3×40 mL water to wash away excess startingmaterial. The organic layer was washed with 30 mL brine, dried overK₂CO₃, and concentrated to yield3-amino-3′-diphenylacetylamino-N-methyldipropylamine as viscous yellowoil (crude 0.82 g, 80%, 2.40 mmol). [M+H] calculated: 340.24, found:340.2.

The crude product obtained above andS-methyl-N-cyano-N′-pyridylisothiourea (0.46 g, 2.40 mmol) weredissolved in 5 ml pyridine. The mixture was stirred at 70° C. for 4hours. Solvent was removed, and the residue was purified by preparativeHPLC to yield the title compound as an off-white solid (0.24 g, 0.5mmol, 21%). ¹H-NMR (DMSO-d6, ppm): 9.58 (br s, 1H), 8.34 (d, 2H), 8.26(M, 2H), 7.84 (br s, 2H), 7.20-7.30 (m, 10H), 4.90 (s, 1H), 3.26 (t,2H), 3.08 (m, 2H), 2.25-2.30 (m, 4H), 2.08 (s, 3H), 1.51-1.63 (m, 4H).ESMS 484.3 (M+1), 506.3 (M+23).

EXAMPLE 20 Naphthalene-2-sulfonic acid(3-{methyl-[3-(N′-cyano-N″-pyridin-4-yl-guanidino)-propyl]-amino}-propyl)-amide(SBR-114492) was synthesized as follows

To a solution of 3,3′-diamino-N-methyldipropylamine (3.05 g, 21.0 mmol,7.0 equiv.) in 10 mL pyridine at room temperature was added slowly2-naphthalenesulfonyl chloride (0.68 g, 3.0 mmol, 1.0 equiv.). Thereaction mixture was stirred at room temperature overnight, diluted with100 mL EtOAc, and washed with 3×40 mL water to wash away excess startingmaterial. The organic layer was washed with 30 mL brine, dried overK₂CO₃, and concentrated to yield3-amino-3′-(2-naphthalenesulfonyl)amino-N-methyldipropylamine as viscouscolorless oil (crude 0.78 g, 77%, 2.32 mmol). [M+H] calculated: 336.18,found: 336.2.

The crude product obtained above andS-methyl-N-cyano-N′-pyridylisothiourea (0.45 g, 2.32 mmol) weredissolved in 5 ml pyridine. The mixture was stirred at 70° C. for 4hours. Solvent was removed, and the residue was purified by preparativeHPLC to yield the title compound as an off-white solid (0.21 g, 0.5mmol, 19%). ¹H-NMR (DMSO-d₆, ppm): 9.58 (br s, 1H), 8.42 (s, 1H), 8.32(d, 2H), 8.14 (t, 2H), 8.03 (d, 1H), 7.77 (dd, 1H),, 7.63-7.72 (m, 3H),7.16 (d, 2H), 3.21 (t, 2H), 2.79 (t, 2H), 2.23 (t, 4H), 2.02 (s, 3H),1.58 (t, 2H), 1.48 (t, 2H). ESMS 480.3 (M+1), 502.3 (M+23).

EXAMPLE 21N-[2-(2-Benzhydryloxy-ethylamino)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4493) was synthesized as follows

To a solution of 2-(2-aminoethylamino)ethanol (2.08 g, 20 mmol, 1.00eq.) in 40 mL MeOH at 0° C. was slowly added ethyl trifluoroacetate(7.10 g, 50 mmol, 2.50 eq.). The mixture was stirred at room temperaturefor 3 hours. Solvent and excess ethyl trifluoroacetate were then removedto yield2-[N-trifluoroacetyl-N-(2-N′-trifluoroacetyl-aminoethyl)-amino]-ethanolas viscous colorless oil (5.90 g, 100%).

2-[N-trifluoroacetyl-N-(2-N′-trifluoroacetyl-aminoethyl)-amino]-ethanol(2.95 g, 10 mmol, 1.00 eq.) and diphenylbromomethane (2.47 g, 10 mmol,1.00 eq.) were dissolved in 50 mL CH₂Cl₂. Triethylamine (1.55 g, 15mmol, 1.50 eq.) was added to the solution at room temperature. Themixture was stirred at room temperature overnight. Usual workup yieldedcolorless viscous oil which was treated with 20 mL 2M NaOH in 50 mL MeOHat room temperature for 3 hours. Most of solvents were removed on rotaryevaporator. EtOAc/aqueous workup gaveN-diphenylmethoxyethyl-ethylenediamine as colorless viscous oil (1.60 g,crude). [M+H] calculated: 271.17, found: 271.1.

The crude product N-diphenylmethoxyethyl-ethylenediamine obtained above(1.60 g, 6.0 mmol, 1.0 equiv.) andS-methyl-N-cyano-N′-pyridylisothiourea (0.576 g, 3.00 mmol, 0.5 equiv.)were dissolved in 5 ml pyridine. The mixture was stirred at 70° C. for 4hours. Solvent was removed, and the residue was purified by preparativeHPLC to yield the title compound as an off-white solid (0.80 g, 1.93mmol, 64%). ¹H-NMR (DMSO-d₆, ppm): 8.24 (d, 2H), 7.11-7.41 (m, 14H),5.45 (s, 1H), 3.49 (t, 2H), 2.58-2.81 (m, 6H), 1.25 (br s, 1H). ESMS415.2 (M+1), 437.3 (M+23).

EXAMPLE 22N-{2-12-(4-Chloro-phenoxy)-ethylsulfanyl]-ethyl}-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4494) was synthesized as follows

To a solution of 2-(2-aminoethylthio)ethanol (3.64 g, 30 mmol, 1.00 eq.)in 20 mL MeOH at 0° C. was slowly added ethyl trifluoroacetate (5.68 g,40 mmol, 1.30 eq.). The mixture was stirred at room temperature for 4hours. Solvent and excess ethyl trifluoroacetate were then removed toyield 2-(2-N-trifluoroacetyl-aminoethylthio)ethanol as red-brown viscousoil (6.50 g, 100%).

2-(2-N-trifluoroacetyl-aminoethylthio)ethanol (1.09 g, 5 mmol, 1.00eq.), 4-chlorophenol (0.771 g, 6 mmol, 1.20 eq.), and PPh₃ (1.70 g, 6.50mmol, 1.30 eq.) were dissolved in 15 mL THF, and the mixture was cooleddown to 0° C. Diethyl azodicarboxylate (1.13 g, 6.50 mmol, 1.30 eq.) wasadded in drops. The mixture was stirred at room temperature for 24hours, then treated with 5 mL 2 M NaOH and 10 mL MeOH for 2 hours. Themixture was concentrated to about 10 mL, diluted with 60 mL EtOAc, andwashed with 2×10 mL 1M NaOH. The organic layer was diluted with 10 mLether and 2 mL hexane, and washed with 3×20 mL 1M HCl. The combinedacidic aqueous layer was treated with NaOH until pH>12, and extractedwith 3×60 mL EtOAc. The combined EtOAc layer was dried over K₂CO₃, andconcentrated to yield 2-[2-(4-chlorophenoxy)ethylthio)]ethylamine aslight yellow viscous oil (crude, 0.98 g, 4.24 mmol, 85%). [M+H]calculated: 232.05, found: 232.0.

The crude product 2-[2-(4-chlorophenoxy)ethylthio)]ethylamine obtainedabove (0.98 g, 4.24 mmol, 1.06 equiv.) andS-methyl-N-cyano-N′-pyridylisothiourea (0.768 g, 4.00 mmol, 1.0 equiv.)were dissolved in 10 ml pyridine. The mixture was stirred at 70° C. for4 hours. The mixture was diluted with 100 mL water. White solid wasformed, collected and washed with 2×3 mL EtOAc. The title compound wasobtained as a white solid (0.73 g, 1.95 mmol, 49%). ¹H-NMR (DMSO-d₆,ppm): 9.50 (br s, 1H), 8.41 (d, 2H), 7.93 (br s, 1H), 7.32 (d, 2H), 7.27(d, 2H), 6.98 (d, 2H), 4.14 (t, 3H), 3.49 (t, 2H), 2.92 (t, 2H), 2.80(t, 2H). ESMS 376.1 (M+l), 398.1 (M+23).

EXAMPLE 23N-[2-(2-Benzhydryloxy-ethylsulfanyl)ethyl]-N′-cyano-″-pyridin-4-yl-guanidine(SBR-11-4495) was synthesized as follows

2-(2-N-trifluoroacetyl-aminoethylthio)ethanol (1.09 g, 5.0 mmol, 1.00eq.) and bromodiphenyl methane (1.236 g, 5.0 mmol, 1.00 eq.) weredissolved in 20 mL CH₂Cl₂. Triethylamine (0.556 g, 5.50 mmol, 1.10 eq.)was added to the solution at room temperature. The mixture was stirredat room temperature overnight. Solvent was removed and the residue wastreated with 15 mL 2 M NaOH in 20 mL MeOH for 2 hours. The mixture wasconcentrated to about 20 ml, diluted with 100 ml EtOAc, and washed with2×20 mL brine. The organic layer was diluted with 10 ml ether and 2 mLhexane, and washed with 3×20 mL 1M HCl. The combined acidic aqueouslayer was treated with NaOH until pH>12, and extracted with 3×60 mLEtOAc. The combined EtOAc layer was dried over K₂CO₃, and concentratedto yield 2-(2-diphenylmethoxyethylthio)ethylamine as light brown viscousoil (crude, 1.10 g, 3.83 mmol, 77%). [M+H] calculated: 288.13, found:288.1.

The crude product 2-(2-diphenylmethoxyethylthio)ethylamine obtainedabove (1.10 g, 3.83 mmol, 0.96 equiv.) andS-methyl-N-cyano-N′-pyridylisothiourea (0.768 g, 4.00 mmol, 1.0 equiv.)were dissolved in 10 ml pyridine. The mixture was stirred at 70° C. for4 hours. The mixture was diluted with 100 mL water and extracted with2×100 ml EtOAc. The organic layer was dried over MgSO₄, concentrated andvacuum dried. Recrystallization in CH₂Cl₂/EtOAc yielded the titlecompound as a white solid (0.51 g, 1.18 mmol, 30%). ¹H-NMR (DMSO-d₆,ppm): 9.55 (br s, 1H), 8;38 (d, 2H), 7.87 (br s, 1H), 7.23-7.39 (m,12H), 5.50 (s, 1H), 3.57(t, 3H), 3.45 (t, 2H), 2.80 (t, 3H), 2.74 (t,2H). ESMS 432.2 (M+1), 454. 2 (M+23).

EXAMPLE 24N-(2-{2-[Bis-(4-fluoro-phenyl)methoxy]-ethoxy}-ethyl)-N′-cyano-N″-pyridin-4-yl-guanidine(SBR-11-4565) was synthesized as follows

To a solution of 2-(2-N-trifluoroacetyl-aminoethoxy)ethanol (2.41 g,12.0 mmol, 1.20 eq.) and 4,4′-difluorobenzhydrol (2.20 g, 10.0 mmol,1.00 eq.) in 30 mL benzene was added slowly 1 mL 98% sulfuric acid atroom temperature. The mixture was stirred at room temperature for 12hours. The reaction mixture was diluted with 10 mL water, neutralizedwith NaOH until pH>13, and extracted with 3×40 mL EtOAc. The combinedorganic layer was concentrated, and the residue was treated with 10 mL2M NaOH in 10 mL MeOH at room temperature for 4 hours. Most of solventswere removed on rotary evaporator. EtOAc/aqueous workup gave2-[2-bis-(4-fluorophenyl)methoxyethoxy]ethylamine as light yellowviscous oil (crude, 2.42 g). [M+H] calculated: 308.12, found: 308.0.

The crude product 2-[2-bis-(4-fluorophenyl)methoxyethoxy]ethylamineobtained above (2.42 g, 7.89 mmol, 1.00 equiv.) andS-methyl-N-cyano-N′-pyridylisothiourea (1.514 g, 7.89 mmol, 1.0 equiv.)were dissolved in 10 ml pyridine. The mixture was stirred at 70° C. for4 hours. Solvent was removed, and the residue was dissolved in 4 mLCH₂Cl₂. The 4 mL ether was added to the solution resulting formation ofyellow solid which was removed by filtration. The solution wasconcentrated and the title product was isolated as yellow solid (0.54 g,1.20 mmol, 12% from 4,4′-difluorobenzhydrol) after flash chromatography.¹H-NMR (DMSO-d₆, ppm): 8.55 (br s, 1H), 8.24 (d, 2H), 7.73 (br s, 1H),7.61 (d, 2H), 7.21-7.24 (m, 4H), 6.95-7.00 (m, 4H), 5.34 (s, 1H),3.58-3.80 (m, 8H). ESMS 452.3 (M+1), 474.2 (M+23).

EXAMPLES 25-148

Each of the pyridyl cyanoguanidine compounds named in the followingtable was prepared in accordance with the methods described above. ¹HNuclear magnetic resonance and mass spectroscopy data of each compoundare also listed below. The columns “Mass (Cald),” “M+1, ” “M (other)”refer to the calculated mass, the measured mass, and the mass associatedwith other ions, e.g., Na⁺, of the exemplified compounds, respectively.

Compound Mass Example ID Name NMR (Cald) M + 1 Mass(other) 25SBR-11-2728 N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.21 390.13 391.1 413.1pyridin-4-yl- (s, 1H), 9.48(bs, 1H), (M + 23) guanidinomethyl)- 8.39(d,2H), 8.32(t, 1H), phenyl)-2-thiophen- 7.57(d, 2H), 7.39(t, 1H),2-yl-acetamide 7.27(d, 2H), 7.22(d, 2H), 6.97(m, 2H), 4.43 (d, 2H) 26SBR-11-2730 N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.52 371.15 372.2pyridin-4-yl- (s, 1H), 9.56(bs, 1H), guanidinomethyl)- 8.78(d, 2H),8.39(m, phenyl)- 2H), 7.85(d, 2H), 7.75 isonicotinamide (d, 2H), 7.23(d,2H), 7.21(d, 2H), 4.47(d, 2H) 27 SBR-11-2744 Benzoic acid 2-(4-(DMSO-d₆, ppm): 10.50 504.19 505.4 527.1 (N′-cyano-N″- (s, 1H), 9.52(bs,1H), (M + 23) pyridin-4-yl- 8.39(bs, 3H), 7.91(d, guanidinomethyl)- 2H),7.51-7.69(m, 7H), phenylcarbamoyl)- 7.39(m, 2H), 7.26(d, benzyl ester2H), 7.22(d, 2H), 5.53(s, 2H), 4.44(d, 2H) 28 SBR-11-27453-(4-Chloro-phenyl)- (DMSO-d₆, ppm): 10.25 430.13 431.2 453.1N-(4-(N′-cyano-N″- (s, 1H), 9.50(bs, 1H), (M + 23) pyridin-4-yl- 8.40(d,2H), 8.33(bs, guanidinomethyl)- 1H), 7.60-7.67(m, 4H),phenyl)-acrylamide 7.50-7.55(m, 3H), 7.30 (d, 2H), 7.22(d, 2H), 6.82(d,1H), 4.45(d, 2H) 29 SBR-11-2747 2-Dimethylamino-N- (DMSO-d₆, ppm):9.77(s, 441.23 442.4 464.2 (4-(N′-cyano-N″- 1H), 9.48(bs, 1H), 8.30 (M +23) pyridin-4-yl- (d, 2H), 8.30(bs, 1H), guanidinomethyl)- 7.53(d, 2H),7.14-7.25 phenyl)-3-phenyl- (m, 9H), 4.41(d, 2H), propionamide 3.42(m,1H), 3.05(m, 1H), 2.87(m, 1H), 2.32 (s, 6H) 30 SBR-11-27482-Furan-2-yl-N-(4- (DMSO-d₆, ppm): 10.83 388.13 389.2 411.1(N′-cyano-N″- (s, 1H), 9.53(bs, 1H), (M + 23) pyridin-4-yl- 8.40(bs,3H), 8.22(d, guanidinomethyl)- 1H), 7.90(d, 1H), 7.77 phenyl)-2-oxo- (d,H), 7.34(d, 2H), 7.22 acetamide (d, 2H), 6.84(m, 1H), 4.46(d, 2H) 31SBR-11-2749 2-(6-Methoxy- (DMSO-d₆, ppm): 10.13 478.21 479.4 501.3naphthalen-2-yl)-N- (s, 1H), 9.03(bs, 1H), (M + 23) (4-(N′-cyano-N″-8.54(d, 2H), 7.78(m, pyridin-4-yl- 3H), 7.58(d, 2H), 7.49guanidinomethyl)- (m, 3H), 7.25(m, 3H), phenyl)- 7.15(d, 1H), 4.46(d,propionamide 2H), 3.96(q, 1H), 3.88(s, 3H), 1.48(d, 3H) 32 SBR-11-27502-Benzyl-N-(4-(N′- (DMSO-d₆, ppm): 10.38 460.20 461.3 483.2cyano-N″-pyridin-4- (s, 1H), 9.52(bs, 1H), (M + 23) yl-guanidinomethyl)-8.41(d, 2H), 8.32(bs, phenyl)-benzamide 1H), 7.67(d, 2H), 7.31 (m, 13H),4.44(d, 2H), 4.14(s, 2H) 33 SBR-11-2751 1-Methyl-1H- (DMSO-d₆, ppm):9.75(s, 373.17 374.3 396.2 pyrrole-2-carboxylic 1H), 9.58(bs, 1H), 8.39(M + 23) acid (4-(N′-cyano- (d, 2H), 8.35(bs, 1H), N″-pyridin-4-yl-7.70(d, 2H), 7.27(d, guanidinomethyl)- 2H), 7.21(d, 2H), 7.01phenyl)-amide (m, 2H), 6.08(m, 1H), 4.45(d, 2H), 3.87(s, 3H) 34SBR-11-2752 Pyridine-2- (DMSO-d₆, ppm): 10.64 371.15 372.2 394.2carboxylic acid (4- (s, 1H), 9.52(bs, 1H), (M + 23) (N′-cyano-N″-8.75(d, 1H), 8.40(d, pyridin-4-yl- 2H), 8.35(bs, 1H), 8.18guanidinomethyl)- (d, 1H), 8.08(t, 1H), 7.89 phenyl)-amide (d, 2H),7.68(t, 1H), 7.33 (d, 2H), 7.23(d, 2H), 4.47(d, 2H) 35 SBR-11-2754N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.30 490.10 491.1 pyridin-4-yl- (bs,1H), 9.49(bs, 1H), guanidinomethyl)- 8.38(d, 2H), 8.22(bs, phenyl)-4-1H), 7.75(d, 2H), 7.62 trifluoromethoxy- (d, 2H), 7.20(d, 4H),benzenesulfonamide 7.08(d, 2H), 4.39(d, 2H) 36 SBR-11-27554-Chloro-N-(4-(N′- (DMSO-d₆, ppm): 10.38 440.08 441.1 463.1cyano-N″-pyridin-4- (bs, 1H), 9.45(bs, 1H), (M + 23)yl-guanidinomethyl)- 8.38(bs, 2H), 8.25(bs, phenyl)- 1H), 7.74(d, 2H),7.62 benzenesulfonamide (d, 2H), 7.22(d, 4H), 7.08(d, 2H), 4.38(d, 2H)37 SBR-11-2756 N-(4-(4-(N′-Cyano- (DMSO-d₆, ppm): 10.29 463.14 464.2486.2 N″-pyridin-4-yl- (s, 1H), 10.19(s, 1H), (M + 23) guanidinomethyl)-9.50(bs, 1H), 8.37(d, phenylsulfamoyl)- 2H), 8.26(t, 1H), 7.69(s,phenyl)-acetamide 4H), 7.18(m, 4H), 7.06 (d, 2H), 4.37(d, 2H), 2.06(s,3H) 38 SBR-11-2757 N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.31 406.12 407.1429.1 pyridin-4-yl- (s, 1H), 9.57(bs, 1H), (M + 23) guanidinomethyl)-8.37(d, 2H), 8.25(t, 1H), phenyl)- 7.76(m, 2H), 7.55(m,benzenesulfonamide 3H), 7.20(m, 4H), 7.05 (d, 2H), 4.36(d, 2H) 39SBR-11-2758 4-Methyl-N-(4-(N′- (DMSO-d₆, ppm): 10.22 420.14 421.2 443.2cyano-N″-pyridin-4- (s, 1H), 9.52(bs, 1H), (M + 23) yl-guanidinomethyl)-8.37(d, 2H), 8.25(t, 1H), phenyl)- 7.63(d, 2H), 7.31(d,benzenesulfonamide 2H), 7.17(m, 4H), 7.06 (d, 2H), 4.36(d, 2H), 2.32(s,3H) 40 SBR-11-2759 4-Chloro-N-(4-(N′- (DMSO-d₆, ppm): 10.69 485.07 486.1508.1 cyano-N″-pyridin-4- (bs, 1H), 9.47(bs, 1H), (M + 23)yl-guanidinomethyl)- 8.50(s, 1H), 8.40(d, 2H), phenyl)-3-nitro- 8.20(bs,1H), 8.18(d, benzenesulfonamide 1H), 7.89(s, 1H), 7.60(d, 2H), 7.21(d,4H), 4.40 (d, 2H) 41 SBR-11-2760 Biphenyl-4-sulfonic (DMSO-d₆, ppm):10.38 482.15 483.2 505.2 acid (4-(N′-cyano- (s, 1H), 9.48(bs, 1H), (M +23) N″-pyridin-4-yl- 8.36(d, 2H), 8.28(t, 1H), guanidinomethyl)- 7.83(s,3H), 7.70(d, 2H), phenyl)-amide 7.46(m, 4H), 7.16(m, 6H), 4.36(d, 2H) 42SBR-11-2761 2,5-Dichloro-N-(4- (DMSO-d₆, ppm): 10.75 474.04 475.0 497.0(N′-cyano-N″- (bs, 1H), 9.60(bs, 1H), (M + 23) pyridin-4-yl- 8.38(d,2H), 8.27(t, 1H), guanidinomethyl)- 7.98(s, 1H), 7.70(m, phenyl)- 2H),7.30(m, 4H), 7.10 benzenesulfonamide (d, 2H), 4.37(d, 2H) 43 SBR-11-2762Naphthalene-2- (DMSO-d₆, ppm): 10.41 456.14 457.3 479.2 sulfonic acid(4-(N′- (s, 1H), 9.53(bs, 1H), (M + 23) cyano-N″-pyridin-4- 8.44(s, 1H),8.34(d, 2H), yl-guanidinomethyl)- 8.21(t, 1H), 8.09(m, phenyl)-amide2H), 7.98(d, 1H), 7.78 (d, 1H), 7.69(m, 2H), 7.15(m, 6H), 4.32(d, 2H) 44SBR-11-2778 1-Methyl- (DMSO-d₆, ppm): 9.49 390.22 391.3cyclohexanecarboxyl- (bs, 1H), 9.17(s, 1H), ic acid (4-(N′-cyano-8.38(d, 2H), 8.31(t, 1H), N″-pyridin-4-yl- 7.60(d, 2H), 7.24(d,guanidinomethyl)- 2H), 7.20(bs, 2H), 4.43 phenyl)-amide (d, 2H), 2.06(m,2H), 1.20-1.48(m, 8H), 1.17 (s, 3H) 45 SBR-11-2780 6-Hydroxy-2,5,7,8-(DMSO-d₆, ppm): 9.54 498.24 499.2 521.1 tetramethyl- (bs, 1H), 9.38(s,1H), (M + 23) chroman-2- 8.37(d, 2H), 8.28(bs, carboxylic acid (4- 1H),7.57(d, 2H), 7.51(s, (N′-cyano-N″- 1H), 7.26(d, 2H), 7.18 pyridin-4-yl-(bs, 2H), 4.34(d, 2H), guanidinomethyl)- 2.58(m, 2H), 2.32(m,phenyl)-amide 1H), 2.21(s, 3H), 2.10(s, 3H), 2.02(s, 3H), 1.82 (m, 1H),1.52(s, 3H) 46 SBR-11-2781 1-Methyl-1H-indole- (DMSO-d₆, ppm): 10.33423.18 424.1 2-carboxylic acid (4- (s, 1H), 9.50(bs, 1H), (N′-cyano-N″-8.40(bs, 2H), 8.33(bs, pyridin-4-yl- 1H), 7.74(d, 2H), 7.70guanidinomethyl)- (d, 1H), 7.57(d, 1H), phenyl)-amide 7.32(d, 4H),7.22(bs, 2H), 7.13(t, 1H), 4.48(d, 2H), 4.03(s, 3H) 47 SBR-11-27825-Methyl-thiophene- (DMSO-d₆, ppm): 10.11 390.13 391.2 2-carboxylic acid(4- (s, 1H), 9.52(bs, 1H), (N′-cyano-N″- 8.40(bs, 2H), 8.34(bs,pyridin-4-yl- 1H), 7.81(d, 1H), 7.68 guanidinomethyl)- (d, 2H), 7.30(d,2H), phenyl)-amide 7.22(bs, 2H), 6.91(d, 2H), 4.45(d, 2H), 2.50(s, 3H)48 SBR-11-2783 8-Hydroxy- (DMSO-d₆, ppm): 11.22 437.16 438.2quinoline-2- (s, 1H), 10.50(bs, 1H), carboxylic acid (4- 9.60(bs, 1H),8.57(d, (N′-cyano-N″- 1H), 8.40(bs, 2H), 8.27 pyridin-4-yl- (d, 1H),7.59(t, 1H), 7.54 guanidinomethyl)- (d, 1H), 7.41(d, 2H), phenyl)-amide7.23(m, 3H), 4.51(d, 2H), 3.50(bs, 1H) 49 SBR-11-2887 2-Phenyl-(DMSO-d₆, ppm): 10.08 432.14 433.3 455.2 ethenesulfonic acid (bs, 1H),9.48(bs, 1H), (M + 23) (4-(N′-cyano-N″- 8.37(bs, 2H), 8.26(t,pyridin-4-yl- 1H), 7.68(m, 3H), 7.41 guanidinomethyl)- (m, 4H),7.16-7.26(m, phenyl)-amide 6H), 4.38(d, 2H) 50 SBR-11-28884-Bromo-N-(4-(N′- (DMSO-d₆, ppm): 10.37 484.05 485.0 507.0cyano-N″-pyridin-4- (bs, 1H), 9.47(bs, 1H), (M + 23)yl-guanidinomethyl)- 8.38(d, 2H), 8.24(d, phenyl)- 2H), 7.76(d, 2H),7.66 benzenesulfonamide (d, 2H), 7.20(d, 4H), 7.06(d, 2H), 4.37(d, 2H)51 SBR-11-2889 2,4,6-Trimethyl-N- (DMSO-d₆, ppm): 10.23 448.17 449.3471.2 (4-(N′-cyano-N″- (s, 1H), 9.06(bs, 1H), (M + 23) pyridin-4-yl-8.57(d, 2H), 7.49(bs, guanidinomethyl)- 2H), 7.19(d, 2H), 6.98 phenyl)-(m, 4H), 4.40(d, 2H), benzenesulfonamide 2.52(s, 6H), 2.21(s, 3H) 52SBR-11-2890 4-Fluoro-N-(4-(N′- (DMSO-d₆, ppm): 10.33 424.11 425.2 447.1cyano-N″-pyridin-4- (s, 1H), 9.50(bs, 1H), (M + 23) yl-guanidinomethyl)-8.37(bs, 2H), 8.24(bs, phenyl)- 1H), 7.81(m, 2H), 7.37benzenesulfonamide (m, 2H), 7.18(m, 4H), 7.06(d, 2H), 4.34(d, 2H) 53SBR-11-2891 4-tert-Butyl-N-(4- (DMSO-d₆, ppm): 10.31 462.18 463.3 485.2(N′-cyano-N″- (bs, 1H), 9.47(bs, 1H), (M + 23) pyridin-4-yl- 8.38(d,2H), 8.25(t, 1H), guanidinomethyl)- 7.70(d, 2H), 7.55(d, phenyl)- 2H),7.19(d, 4H), 7.09 benzenesulfonamide (d, 2H), 4.36(d, 2H), 1.25(s, 9H)54 SBR-11-2892 Quinoline-8-sulfonic (DMSO-d₆, ppm): 10.05 457.13 458.1480.1 acid (4-(N′-cyano- (bs, 1H), 9.45(bs, 1H), (M + 23)N″-pyridin-4-yl- 9.12(d, 1H), 8.52(d, guanidinomethyl)- 1H), 8.33(m,3H), 8.24 phenyl)-amide (d, 1H), 8.11(t, 1H), 7.71 (m, 2H), 7.11(bs,2H), 7.03(s, 4H), 4.26(d, 2H) 55 SBR-11-2893 4-Iodo-N-(4-(N′- (DMSO-d₆,ppm): 10.35 532.02 533.0 cyano-N″-pyridin-4- (bs, 1H), 9.47(bs, 1H),yl-guanidinomethyl)- 8.38(d, 2H), 8.24(t, 1H), phenyl)- 7.91(d, 2H),7.48(d, benzenesulfonamide 2H), 7.19(d, 4H), 7.05 (d, 2H), 4.37(d, 2H)56 SBR-11-2894 N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 9.83 420.14 421.2443.1 pyridin-4-yl- (bs, 1H), 9.52(bs, 1H), (M + 23) guanidinomethyl)-8.39(d, 2H), 8.32(t, 1H), phenyl)-C-phenyl- 7.16-7.34(m, 11H), 4.44methanesulfonamide (bs, 4H) 57 SBR-11-2895 4-Methoxy-N-(4-(N′- (DMSO-d₆,ppm): 10.13 436.13 437.2 459.1 cyano-N″-pyridin-4- (bs, 1H), 9.52(bs,1H), (M + 23) yl-guanidinomethyl)- 8.36(d, 2H), 8.23(t, 1H), phenyl)-7.68(d, 2H), 7.17(d, benzenesulfonamide 4H), 7.05(m, 4H), 4.36 (d, 2H),3.78(s, 3H) 58 SBR-11-2896 2-Bromo-N-(4-(N′- (DMSO-d₆, ppm): 10.62484.05 485.1 506.9 cyano-N″-pyridin-4- (bs, 1H), 9.47(bs, 1H), (M + 23)yl-guanidinomethyl)- 8.37(d, 2H), 8.21(t, 1H), phenyl)- 8.05(d, 1H),7.79(d, benzenesulfonamide 1H), 7.53(m, 2H), 7.16 (d, 4H), 7.06(d, 2H),4.34(d, 2H) 59 SBR-11-2898 N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.62451.11 452.2 474.1 pyridin-4-yl- (bs, 1H), 9.47(bs, 1H), (M + 23)guanidinomethyl)- 8.37(d, 4H), 8.24(t, 1H), phenyl)-4-nitro- 7.98(d,2H), 7.20(d, benzenesulfonamide 4H), 7.07(d, 2H), 4.37 (d, 2H) 60SBR-11-2899 N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.52 474.11 475.2 497.1pyridin-4-yl- (s, 1H), 9.18(bs, 1H), (M + 23) guanidinomethyl)- 8.60(d,2H), 8.02(m, phenyl)-3- 3H), 7.80(t, 1H), 7.53 trifluoromethyl- (bs,2H), 7.23(d, 2H), benzenesulfonamide 7.12(d, 2H), 4.46(d, 2H) 61SBR-11-2900 Naphthalene-1- (DMSO-d₆, ppm): 10.74 456.14 457.3 479.1sulfonic acid (4-(N′- (s, 1H), 9.10(bs, 1H), (M + 23)cyano-N″-pyridin-4- 8.72(d, 1H), 8.57(d, yl-guanidinomethyl)- 2H),8.23(m, 2H), 8.08 phenyl)-amide (d, 1H), 7.64(m, 4H), 7.50(bs, 2H),7.12(d, 2H), 7.02(d, 2H), 4.38 (d, 2H) 62 SBR-11-3211 4-Chloro-N-(4-(N′-(DMSO-d₆, ppm): 10.38 504.11 505 526.9 cyano-N″-(2-methyl- (bs, 1H),9.45(bs, 1H), (M + 23) quinolin-4-yl)- 8.25(bs, 1H), 8.08(m,guanidinomethyl)- 1H), 7.75(d, 1H), 7.70 phenyl)- (d, 2H), 7.62(d, 2H),benzenesulfonamide 7.52(t, 1H), 7.29(t, 1H), 7.22(d, 2H), 7.08(d, 2H),6.98(s, 1H), 4.40(d, 2H), 2.50(s, 3H) 63 SBR-11-3401 4-Chloro-N-(4-(N′-(DMSO-d₆, ppm): 10.33 454.13 455.1 cyano-N″-quinolin- (s, 1H), 9.42(s,1H), 8.95 5-yl- (s, 1H), 8.18(m, 1H), guanidinomethyl)- 8.01(d, 2H),7.46-7.86 phenyl)-benzamide (m, 9H), 7.27(d, 2H), 4.36(d, 2H) 64SBR-11-3402 4-Chloro-N-(4-(N′- (DMSO-d₆, ppm): 10.15 468.15 469cyano-N″-(2-methyl- (bs, 1H), 9.44(bs, 1H), quinolin-4-yl)- 8.22(bs,1H), 8.08(m, guanidinomethyl)- 1H), 7.75(d, 1H), 7.69 phenyl)-benzamide(d, 2H), 7.55(d, 2H), 7.50(t, 1H), 7.28(t, 1H), 7.21(d, 2H), 7.10(d,2H), 6.99(s, 1H), 4.41(d, 2H), 2.49(s, 3H) 65 SBR-11-35381-Benzoyl-3-(4-(N′- (DMSO-d₆, ppm): 429.50 430.1 cyano-N″-pyridin-4-10.58(s, 1H), 9.45(s, 1H), yl-guanidinomethyl)- 8.42(m, 3H), 7.91(d,2H), phenyl)-thiourea 7.70(m, 3H), 7.58(d, 2H), 7.38(d, 2H), 7.20(s,2H), 4.45(d, 2H) 66 SBR-11-3547 N-Cyano-N′-(4- (DMSO-d₆, ppm): 9.42406.19 407.2 ((naphthalen-1- (bs, 1H), 8.38(d, 2H), ylmethyl)-amino)-8.14(d, 2H), 7.94(d, benzyl)-N″-pyridin- 1H), 7.82(d, 1H), 7.40-4-yl-guanidine 7.64(m, 4H), 7.18(d, 2H), 7.08(d, 2H), 6.62 (d, 2H),6.28(t, 1H), 4.69 (d, 2H), 4.34(d, 2H) 67 SBR-11-3548 N-(4-(3,5-Di-tert-(DMSO-d₆, ppm): 9.41 484.3 485.3 butyl-4-hydroxy- (bs, 1H), 8.35(d, 2H),benzylamino)- 8.13(bs, 1H), 7.18(m, benzyl)-N′-cyano- 2H), 7.10(s, 2H),7.06(d, N″-pyridin-4-yl- 2H), 6.80(s, 1H), 6.60(d, guanidine 2H),5.97(t, 1H), 4.32(d, 2H), 4.06(d, 2H), 1.38(s, 18H) 68 SBR-11-35502-(6-Methoxy- (DMSO-d₆, ppm): 10.16 478.21 479.4 naphthalen-2-yl)-N- (s,1H); 9.04(bs, 1H); (4-(N′-cyano-N″- 8.54(d, 2H); 7.80(m, pyridin-4-yl-3H); 7.60(d, 2H); guanidinomethyl)- 7.48(m, 3H); 7.23(d, phenyl)- 2H);7.16(d, 2H); 4.44 propionamide (d, 2H); 3.99(q, 1H); 3.85(s, 3H);1.50(d, 3H); 69 SBR-11-3611 Acetic acid 2-(4-(N′- (CDCl₃, ppm) 8.36(bs.540.61 541.3 cyano-N″-pyridin-4- 1H); 7.98(d, 2H); yl-guanidinomethyl)-7.45(bs. 2H); 7.31(d, 2H); phenylcarbamoyl)- 7.21(d, 2H); 4.61(bs.2,5,6,8-tetramethyl- 2H); 2.55(m, 2H); 2.26 chroman-7-yl ester (s, 3H);2.16(s, 3H); 1.99 (s, 3H); 1.94(m, 2H); 1.89 (s, 3H); 1.50(s, 3H); 70SBR-11-3665 N-(4-(2-Benzyloxy- (DMSO-d₆, ppm) 9.41 462.22 463.2benzylamino)- (bs, 1H), 8.32(d, 2H), benzyl)-N′-cyano- 8.13(bs, 1H),7.51-6.82 N″-pyridin-4-yl- (several m, 16H), 6.53(d, guanidine 2H),6.28(app t, 1H), 5.06(s, 2H), 4.32(d, 2H), 4.21(d, 2H) 71 SBR-11-3666N-(4-(4-Chloro- (DMSO-d₆, ppm) 9.38 390.14 391.1 benzylamino)- (bs, 1H),8.37(d, 2H), benzyl)-N′-cyano- 8.26(bs, 1H), 7.30(s, N″-pyridin-4-yl-4H), 7.20(bs, 2H), 7.03 guanidine (d, 2H), 6.51(d, 2H), 6.30(app t, 1H),4.35(d, 2H), 4.21(d, 2H). 72 SBR-11-3671 Toluene-4-sulfonic (CDCl₃/CD₃ODppm): 415.17 416.3 acid 6-(N′-cyano-N″- 8.38(d, 2H); 7.80(m,pyridin-4-yl- 2H); 7.73(d, 2H); 3.96(t, guanidino)-hexyl 2H); 3.49(t,2H); 2.43(s, ester 3H); 1.62(m, 4H); 1.33 (m, 4H); 73 SBR-11-3703N-Cyano-N′-(4-((1- (DMSO-d₆, ppm): 9.40 409.49 432.1 methyl-1H-indol-3-(bs, 1H), 8.35(d, 2H), (M + 23) ylmethyl)-amino)- 8.14(bs, 1H), 7.75(d,benzyl)-N″-pyridin- 1H), 7.30-7.47(m, 3H), 4-yl-guanidine 7.28(s, 1H),7.18(d, 2H), 7.06(d, 2H), 6.60(d, 2H), 5.95(t, 1H), 4.45(d, 2H), 4.07(d,2H), 3.75(s, 3H) 74 SBR-11-3722 5-Dimethylamino- (CDCl₃ ppm): 8.52(d,494.61 495.2 naphthalene-1- 1H); 8.37(d, 2H); 8.15 sulfonic acid 6-(N′-(m, 2H); 7.48(m, 2H); cyano-N″-pyridin-4- 7.19-7.11(m, 3H); 5.89yl-guanidino)-hexyl (br.t. 1H); 3.89(t, 2H); ester 3.22 9m, 2H); 2.81(s,6H); 1.69-1.10(m, 8H); 75 SBR-11-3723 6-(N′-Cyano-N″- (DMSO-d₆, ppm):412.57 413.3 pyridin-4-yl- 8.38(bs, 2H), 7.85(bs, 1H),guanidino)-hexanoic 7.70(bs, 1H), 7.20(s, 2H), acid (3,7-dimethyl-5.07(s, 1H), 3.25(s, 2H), oct-6-enyl)-amide 3.03(bs, 2H), 1.95(d, 4H),1.64(s, 3H), 1.56(s, 3H) 1.51-1.13(m, 10H) 76 SBR-11-37261-(4-(N′-Cyano-N″- (DMSO-d₆, ppm); 446.49 447.1 pyridin-4-yl- 10.25(bs,2H), guanidinomethyl)- 9.35(bs, 1H), 8.20(d, 2H), phenyl)-3-(4-nitro-8.18(bs, 1H), 8.00(d, 2H), phenyl)-thiourea 7.65(d, 2H), 7.28(d, 2H),7.12(d, 2H), 7.05(bs, 2H), 4.22(d, 2H), 77 SBR-11-3828N-Cyano-N′-pyridin- (DMSO-d₆, ppm): 437.52 438.1 4-yl-N″-(2-(1-(2,4,6-9.45(bs, 1), 8.40(m, 3H), trimethyl- 7.85(s, 1H), 7.40(s, 1H),benzenesulfonyl)- 7.20(m, 3H), 7-15(s, 1H), 1H-imidazol-4-yl)- 3.55(m,2H), 2.74(t, 2H), ethyl)-guanidine 2.55(s, 6H), 2.30(s, 3H) 78SBR-11-3829 N-(2-(1-(5- (DMSO-d₆, ppm): 488.57 489.2 Dimethylamino-9.38(bs, 1H), 8.62(d, 1H), naphthalene-1- 8.52(s, 1H), 8.41(d, 1H),sulfonyl)-1H- 8.29(m, 2H), 8.24(d, 1H), imidazol-4-yl)- 7.83(bs, 1H),7.75(m, 1H), ethyl)-N′-cyano-N″- 7.66(m, 1H), 7.56(s, 1H), pyridin-4-yl-7.29(d, 1H), 7.08(bs, 1H), guanidine 3.47(m, 2H), 2.81(s, 6H), 2.69(t,2H), 79 SBR-11-3830 N-Cyano-N′-(2-(1- (DMSO-d₆, ppm): 445.5 446.1(naphthalene-1- 9.40(bs, 1H), 8.65(d, 1H), sulfonyl)-1H- 8.56(s, 1H),8.44(m, 2H), imidazol-4-yl)- 8.31(bs, 2H), 8.16(d, 2H),ethyl)-N″-pyridin-4- 7.80(m, 2H), 7.72(d, 1H), yl-guanidine 7.59(s, 1H),7.09(bs, 2H), 3.47(m, 2H), 2.70(bs, 2H) 80 SBR-11-38631-(4-(N′-Cyano-N″- (CD₃OD, ppm): 8.33(d, 475.5 476.3 pyridin-4-yl- 2H);7.42(d, 2H); 7.27 guanidinomethyl)- (m, 4H); 6.77(s, 2H);phenyl)-3-(3,4,5- 4.51(s, 2H); 3.80(s, 6H); trimethoxy-phenyl)- 3.71(s,3H) urea 81 SBR-11-3891 N-(2-(3,4-Bis- (CDCl₃, ppm): 8.36 478.2 500.4benzyloxy-phenyl)- (dd, 2H), 7.45-7.24 ethyl)-N′-cyano-N″- (m, 13H),6.80(dd, 2H), pyridin-4-yl- 5.14(d, 4H), 3.35 guanidine (dd, 2H),2.79(app t 2H) 82 SBR-11-3938 2,4,6-Trimethyl-N- (DMSO-d₆, ppm): 10.16448.17 449.2 471.2 (4-(N′-cyano-N″- (bs, 1H), 9.18(bs, 1H), (M + 23)pyridin-3-yl- 8.41(s, 1H), 8.36(d, 1H), guanidinomethyl)- 7.79(t, 1H),7.64(d, 1H), phenyl)- 7.37(m, 1H), 7.12(d, benzenesulfonamide 2H),6.97(m, 4H), 4.30 (d, 2H), 2.58(s, 6H), 2.24 (s, 3H) 83 SBR-11-3941N-(4-(N′-Cyano-N″- (DMSO-d₆, ppm): 10.42 474.11 475.1 497.1pyridin-3-yl- (s, 1H), 9.19(s, 1H), 8.44 (M + 23) guanidinomethyl)- (s,1H), 8.36(d, 1H), 8.03 phenyl)-3- (m, 3H), 7.81(m, 2H), trifluoromethyl-7.64(d, 1H), 7.38(m, benzenesulfonamide 1H), 7.21(d, 2H), 7.08 (d, 2H),4.34(d, 2H) 84 SBR-11-3955 N-(2-(4-(10,11- (CDCl₃, ppm): 8.02 474.2Dihydro-5H- (d, 2H), 7.95(d, 2H), dibenzo(a, d)cyclo- 7.64-7.39(m, 8H),7.38 hepten-5-yloxy)- (d, 2H), 6.84(d, 2H), phenyl)-ethyl)-N′- 6.37(s,1H), 3.96 cyano-N″-pyridin-4- (dd, 2H), 3.08-2.97 yl-guanidine (m, 6H)85 SBR-11-3956 N-(2-(5-Benzyloxy- (DMSO-d₆, ppm): 411.1 1H-indol-3-yl)-10.70(s, 1H), 8.86 ethyl)-N′-methyl-N″- (s, 1H), 8.46(d, 2H),pyridin-4-yl- 7.49-7.30(m, 8H), guanidine 7.17(d, 2H), 6.76 (d, 1H),5.08(s, 2H), 3.24(dd, 2H), 2.96 (app t, 2H) 86 SBR-11-3982Naphthalene-1- (DMSO-d₆, ppm): 442.49 443 sulfonic acid (4-(N′-10.75(bs, 1H), cyano-N″-pyridin-4- 9.73(bs, 1H), 8.73(dd, 1H),yl-guanidino)- 8.35(m, 1H), 8.21(d, 2H), phenyl)-amide 8.08(m, 1H),7.65(m, 4H), 7.19(m, 1H), 7.14(d, 1H), 7.12(d, 1H), 7.01(d, 1H), 6.98(m,1H), 87 SBR-11-3983 5-Dimethylamino- (DMSO-d₆, ppm): 513.62 514.2naphthalene-1- 10.60(bs, 1H), sulfonic acid (4-(2- 9.35(bs, 1H), 8.42(d,1H), (N′-cyano-N″- 8.37(d, 1H), 8.28(d, 2H), pyridin-4-yl- 8.19(d, 1H),7.77(t, 1H), guanidino)-ethyl)- 7.59(q, 2H), 7.23(d, 1H), phenyl)-amide7.07(s, 1H), 7.04(s, 2H), 7.00(s, 2H), 6.97(s, 1H), 3.41(m, 2H),2.74(bs, 6H), 2.69(t, 2H), 88 SBR-11-3984 5-Dimethylamino- (DMSO-d₆,ppm): 513.62 514.2 naphthalene-1- 9.85(s, 1H), 9.46(s, 1H), sulfonicacid (4-(N′- 8.46(d, 1H), 8.39(d, 2H), cyano-N″-pyridin-4- 8.01(d, 1H),7.58(m, 2H), yl-guanidino)-2,5- 7.27(m, 2H), 7.25(s, 1H),dimethyl-phenyl)- 6.90(s, 1H), 6.83(s, 1H), amide 2.83(s, 6H), 2.01(s,3H), 1.81(s, 3H), 89 SBR-11-3987 5-Dimethylamino- (DMSO-d₆, ppm): 485.56486.2 naphthalene-1- 10.65(bs, 1H), sulfonic acid (4-(N′- 9.74(bs, 1H),8.45(d, 1H), cyano-N″-pyridin-4- 8.38(d, 1H), 8.33(bs, 1H),yl-guanidino)- 8.22(d, 1H), 7.62(q, 2H), phenyl)-amide 7.25(d, 2H),7.15(d, 4H), 7.02(d, 2H), 2.81(bs, 6H) 90 SBR-11-3988 5-Dimethylamino-(DMSO-d₆, ppm): 529.61 530.4 naphthalene-1- 10.58(s, 1H), 8.87(s, 1H),sulfonic acid (4-(N′- 8.39(d, 1H), 8.32(d, 1H), cyano-N″-(6- 8.15(d,1H), 7.93(d, 1H), methoxy-pyridin-3- 7.57(q, 2H), 7.47(dd, 1H), yl)-7.35(bs, 1H), 7.20(d, 1H), guanidinomethyl)- 6.96(q, 4H), 6.75(d, 1H),phenyl)-amide 4.13(d, 2H), 3.79(s, 3H), 2.76(s, 6H) 91 SBR-11-39965-Dimethylamino- (DMSO-d₆, ppm); 534.03 534.2 naphthalene-1- 10.63(bs,1H), sulfonic acid (4-(N′- 9.08(bs, 1H), 8.43(d, 1H),(2-chloro-pyridin-3- 8.36(d, 1H), 8.26(dd, 1H), yl)-N″-cyano- 8.19(d,1H), 7.77(d, 1H), guanidinomethyl)- 7.60(q, 2H), 7.42(dd, 1H),phenyl)-amide 7.24(d, 1H), 7.07(d, 2H), 7.02(d, 2H), 4.20(d, 2H),2.79(s, 6H), 92 SBR-11-3997 5-Dimethylamino- (DMSO-d₆, ppm): 514.6 515.2naphthalene-1- 8.43(d, 1H), 8.36(d, 1H), sulfonic acid (4-(N′- 8.19(d,1H), 7.98(bs, 1H), (4-amino-pyridin-3- 7.68(d, 1H), 7.60(q, 2H),yl)-N″-cyano- 7.41(bs, 1H), 7.24(d, 1H), guanidinomethyl)- 7.07(d, 2H),6.98(d, 2H), phenyl)-amide 6.85(bs, 1H), 5.16(bs, 2H), 4.18(d, 2H),2.80(s, 6H) 93 SBR-11-4077 Octane-1-sulfonic (DMSO-d₆, ppm): 9.80(s,442.22 443.2 acid (4-(N′-cyano- 1H), 9.19(bs, 1H), 8.59 N″-pyridin-4-yl-(d, 2H), 7.54(bs, 2H), guanidinomethyl)- 7.32(d, 2H), 7.19(d,phenyl)-amide 2H), 4.50, (d, 2H), 3.05 (app t, 2H), 1.64(pent, 2H),1.30-1.20(m, 10H), 0.84(t, 3H) 94 SBR-11-4078 Hexadecane-1- (DMSO-d₆,ppm): 9.79(s, 554.34 555.4 sulfonic acid (4-(N′- 1H), 9.07(br S, 1H),8.57 cyano-N″-pyridin-4- (d, 2H), 7.51(br S, 2H), yl-guanidinomethyl)-7.30(d, 2H), 7.19(d, phenyl)-amide 2H), 4.48, (d, 2H), 3.04 (app t, 2H),1.63(pent, 2H), 1.20(m, 26H), 0.87 (t, 3H) 95 SBR-21-0660 Piperidine-2-(DMSO-d₆, ppm): 10.15 377.20 378.2 carboxylic acid (4- (s, 1H), 9.53(bs,1H), (N′-cyano-N″- 9.20(bs, 1H), 8.40(d, pyridin-4-yl- 2H), 8.23(bs,1H), 7.56 guanidinomethyl)- (d, 2H), 7.22(d, 4H), phenyl)-amide 4.38(d,2H), 3.89(bs, 1H), 3.20(d, 1H), 2.88 (bs, 1H), 2.15(d, 1H), 1.63(m, 5H)96 SBR-21-2201 Naphthalene-2- (CDCl₃ ppm): 8.80(d, 381.27 382 sulfonicacid 6-(N′- 1H); 8.22(m, 3H); 8.07 cyano-N″-pyridin-4- (d, 1H); 7.89(m,3H); yl-guanidino)-hexyl 7.55(m, 4H); 3.53(m, ester 2H); 3.43(t, 2H);1.61- 1.43(m, 4H); 1.26(m, 4H); 97 SBR-21-2419 N-(4-((8-Hydroxy-(DMSO-d₆, ppm) 9.68 423.18 446.1 quinolin-2- (bs, 1H), 9.37(bs, 1H),(M + 23) ylmethyl)-amino)- 8.39(d, 2H), 8.20(d, benzyl)-N′-cyano- 2H),8.17(m, 2H), 7.55 N″-pyridin-4-yl- (d, 1H), 7.39(m, 2H), guanidine7.21(d, 2H), 7.16(d, 2H), 6.68(d, 2H), 4.57 (d, 2H), 4.31(d, 2H) 98SBR-21-2803 1-(2-Methyl-4-nitro- (DMSO-d₆): 9.44(bs. 444.17 445.2phenyl)-3-(4-(N′- 1H); 8.38(d, 2H); 8.30(m, cyano-N″-pyridin-4- 2H);8.10(d, 2H); yl-guanidinomethyl)- 7.95(s, 1H); 7.47(d, 2H); phenyl)-urea7.29(d, 2H); 7.19(m, 1H); 4.40(bs, 2H); 2.18(s, 3H): 99 SBR-21-28041-(4-(N′-Cyano-N″- (CD₃OD, ppm): 8.30(d, 379.46 380.2 pyridin-4-yl- 2H);7.22(m, 4H); 7.06 guanidinomethyl)- (d, 2H); 4.38(s, 2H); 3.13phenyl)-3-pentyl- (t, 2H); 1.47-1.24(m, urea 6H); 0.88(t, 3H); 100SBR-21-2806 1-(4-(N′-Cyano-N″- (CD₃OD, ppm): 8.34(d, 413.2 414.3pyridin-4-yl- 2H), 7.28-7.55(m, 7H), guanidinomethyl)- 7.25(m, 4H),4.52(s, phenyl)-3-(1-phenyl- 2H), 3.50(q, 1H), 1.50 ethyl)-urea (d, 3H)101 SBR-21-2807 2-Methyl-N-(4-(N′- (DMSO-d₆): 9.03(bs 1H); 519.46 520.2cyano-N″-pyridin-4- 8.63(d, 1H); 8.54(d, yl-guanidinomethyl)- 2H);8.22(d, 2H); 7.50 phenyl)-4- (m, 2H); 7.29(d, 2H); trifluoromethyl-7.13(d, 2H); 4.48(d, 2H) benzenesulfonamide 102 SBR-11-2599 N-(1-Benzyl-(DMSO-d₆, ppm): 334.19 335.3 357.3 piperidin-4-yl)-N′- 9.44(bs, 1H);8.37(d, (M + 23) cyano-N″-pyridin-4- 2H); 7.81(bs, 1H); 7.02-yl-guanidine 7.32(m, 7H); 3.68(m, 1H); 3.45(s, 2H); 2.79 (m, 2H);2.01(m, 2H); 1.82(m, 2H); 1.52(m, 2H) 103 SBR-11-2733N-(4-(4-Benzhydryl- (DMSO-d₆, ppm): 9.71 467.28 468.3 490.3piperazin-1-yl)- (bs, 1H); 8.34(d, 2H); (M + 23) butyl)-N′-cyano-8.11(bs, 1H); 7.40(d, N″-pyridin-4-yl- 4H); 7.49(m, 4H); 7.20 guanidine(m, 4H); 4.22(s, 1H); 3.42(m, 4H); 2.24-2.47 (m, 8H); 1.39-1.60(m, 4H)104 SBR-11-3539 N-(2-(4-Benzyl- (CDC₁₃, ppm): 8.49(dd, 362.2 363.2piperidin-1-yl)- 2H); 7.33-7.20(m, 5H); ethyl)-N′-cyano- 7.12(dd, 2H);6.41(s, N″-pyridin-4-yl- 1H); 3.52-3.43(m, 2H); guanidine 3.05(dd, 2H);2.66-2.57 (m, 4H); 2.18(app t, 2H); 1.76-1.66(m, 2H); 1.36- 1.27(m, 3H)105 SBR-11-3775 N-(3-(4-Benzyl- (CDC₁₃, ppm): 8.60(dd, 376.24 377.2piperidin-1-yl)- 2H); 7.33-7.10(m, 7H); propyl)-N′-methyl- 4.23(dd, 1H);3.51(dd, N″-pyridin-4-yl- 2H); 2.93(dd, 2H); 2.59- guanidine 2.37(m,4H); 1.97-1.20 (m, 9H) 106 SBR-11-4089 5-Dimethylamino- (DMSO-d₆, ppm):9.82 513.19 514.1 naphthalene-1- (bs. 1H); 8.36(m, 3H); sulfonic acid(4-(N″- 8.26(t, 1H); 7.97(d, 1H); pyridin-4-yl- 7.55(m, 2H); 7.23(d,guanidinomethyl)-3- 2H); 7.16(d, 2H); 6.98(d, methyl-phenyl)- 1H);6.89(d, 1H); 4.35 amide (d, 2H); 2.82(s, 6H); 1.89 (s, 3H); 107SBR-11-4084 N-(1-(5- (DMSO-d₆, ppm): 10.0 510.57 511.1 Dimethylamino-(bs, 1H); 9.34(s, 1H); naphthalene-1- 8.61(t, 2H); 8.33(s, 2H);sulfonyl) 1H- 8.22(d, 1H); 7.79(t, 1H); indazol-5-yl)-N′- 7.71(s, 1H);7.56(m, cyano-N″-pyridin-4- 2H); 7.31(d, 1H); 7.20 yl-guanidine (d, 2H);2.76(s, 6H); 108 SBR-11-3940 5-Dimethylamino- (DMSO-d₆, ppm): 10.64499.18 500.3 522.1 naphthalene-1- (bs, 1H), 9.15(bs, 1H), (M + 23)sulfonic acid (4-(N′- 8.42(mt, 3H), 8.33(m, cyano-N″-pyridin-3- 1H),8.20(d, 1H), 7.73 yl-guanidinomethyl)- (bs, 1H), 7.59(m, 3H),phenyl)-amide 7.33(m, 1H), 7.23(d, 1H), 7.08(d, 2H), 7.01 (d, 2H),4.27(d, 2H), 2.83(s, 6H) 109 SBR-11-3939 Naphthalene-1- (DMSO-d₆, ppm):10.65 456.14 457.2 479.1 sulfonic acid (4-(N′- (bs, 1H), 9.15(bs, 1H),(M + 23) cyano-N″-pyridin-3- 8.73(d, 1H), 8.40(s, 1H),yl-guanidinomethyl)- 8.34(d, 1H), 8.20(d, phenyl)-amide 2H), 8.06(d,1H), 7.65 (m, 5H), 7.34(m, 1H), 7.07(d, 2H), 6.98(d, 2H), 4.24(d, 2H)110 SBR-11-4096 5-Dimethylamino- (CDCl₃ ppm): 8.43(dd, 529.19 530.1naphthalene-1- 3H); 8.29(d, 1H); 8.12 sulfonic acid (4-(N′- (dd, 1H);7.54(dd, 1H); cyano-N″-pyridin-4- 7.37(m, 2H); 7.13(d,yl-guanidinomethyl)- 1H); 7.03(dd, 2H); 6.70 2-methyl-phenyl)- (dd, 1H);6.60(d, 1H); amide 4.34(d, 2H); 3.42(s, 3H); 2.82(s, 6H) 111 SBR-11-2733N-[4-(4-Benzhydryl- (DMSO-d₆, ppm): 9.71 467.28 468.3 490.3piperazin-1-yl)- (bs, 1H), 8.34(d, 2H), (M + 23) butyl]-N′-cyano-N″-8.11(bs, 1H), 7.40(m, pyridin-4-yl- 4H), 7.13-7.36(m, 8H), guanidine4.22(s, 1H), 3.42(m, 2H), 2.24-2.47(m, 8H), 1.39-1.60(m, 4H) 112SBR-11-4149 N-[2-(4- (CD₃OD, ppm): 8.39(d, 436.24 437.4 459.2Benzhydrylidene- 2H), 7.42(d, 2H), 7.09- (M + 23) piperidin-1-yl)-7.29(m, 10H), 3.51(t, ethyl]-N′-cyano-N″- 2H), 2.64(m, 6H), 2.41pyridin-4-yl- (m, 4H) guanidine 113 SBR-11-4344 4-[(Bis-naphthalen-(DMSO-d₆, ppm): 10.05 538.28 539.5 561.4 1-ylmethyl-amino)- (bs, 1H),8.10(b, 2H), (M + 23) methyl]-N-cyano-N′- 7.82-7.93(m, 6H), 7.54pyridin-4-yl- (d, 2H), 7.45(m, 4H), piperidine-1- 7.22(t, 2H), 6.63(b,2H), carboxamidine 3.99(s, 4H), 3.72(d, 2H), 2.83(t, 2H), 2.37(d, 2H),1.92(m, 1H), 1.60(d, 2H), 0.64(m, 2H) 114 SBR-11-4407 N-{2-[4-(10,11-(CD₃OD, ppm): 8.40(d, 465.26 466.3 Dihydro-5H- 2H), 7.18-7.43(m, 10H),dibenzo[a,d]cyclo- 4.30(s, 1H), 3.47-3.60 hepten-5-yl)-piperazin- (m,4H), 3.45(t, 2H), 1-yl]-ethyl}-N′- 2.45-2.61(m, 10H) cyano-N″-pyridin-4-yl-guanidine 115 SBR-11-4410 N-{2-[4-(2,2- (CD₃OD, ppm): 8.38(d, 453.26454.5 476.3 Diphenyl-ethyl)- 2H), 7.40(d, 2H), 7.14- (M + 23)piperazin-1-yl]- 7.29(m, 10H), 4.22(t, ethyl}-N′-cyano-N″- 1H), 3.46(t,2H), 3.03(d, pyridin-4-yl- 2H), 2.50-2.60(m, 10H) guanidine 116SBR-11-4482 N-{2-[4-(4-Chloro- (CD₃OD, ppm): 8.40(d, 398.16 399.2 421.2phenoxy)-piperidin-1 2H), 7.42(d, 2H), 7.25(d, (M + 23)yl]-ethyl}-N′-cyano- 2H), 6.92(d, 2H), 4.46 N″-pyridin-4-yl- (m, 1H),3.55(t, 2H), 2.92 guanidine (m, 2H), 2.73(t, 2H), 2.60 (m, 2H), 2.04(m,2H), 1.85(m, 2H) 117 SBR-11-4488 N-[3-(4- (CD₃OD, ppm): 8.36(d, 468.26469.4 Benzhydryloxy- 2H), 7.18-7.50(m, 12H), piperidin-1-yl)- 5.56(s,1H), 3.52(m, 1H), propyl]-N′-cyano-N″- 3.42(t, 2H), 2.76(m, 2H),pyridin-4-yl- 2.43(t, 2H), 2.21(m, 2H), guanidine 1.85(m, 2H), 1.80(m,2H), 1.70(m, 2H) 118 SBR-11-4490 4-(N′-Cyano-N″- (CD₃OD, ppm): 8.51(d,453.23 454.2 476.2 pyridin-4-yl- 2H), 7.63(bs, 2H), 6.95- (M + 23)guanidinomethyl)- 7.40(m, 10H), 4.04(d, piperidine-1- 2H), 3.34((m, 2H),2.75 carboxylic acid (m, 2H), 1.83(m, 2H), diphenylamide 1.66(m, 2H),1.11(m, 2H) 119 SBR-11-4496 N-Cyano-N′-pyridin- (DMSO-d₆, ppm): 9.55(br355.15 378.1 4-yl-N″-[2-(2-p- s, 1H), 8.38(d, 2H), 7.88 (M + 23)tolyloxy- (br s, 1H), 7.25(d, 2H), ethylsulfanyl)-ethyl]- 7.08(d, 2H),6.83(d, 2H), guanidine 4.10(t, 2H), 3.48(t, 3H), 2.90(t, 2H), 2.80(t,2H). 120 SBR-11-4497 N-{2-[4-(2- (CD₃OD, ppm): 8.30(d, 482.28 483.4505.4 Benzhydryloxy- 2H), 7.38(d, 2H), 7.15- (M + 23)ethyl)-piperidin-1-yl] 7.30(m, 10H), 5.32(s, ethyl}-N′-cyano-N″- 1H),3.50(m, 2H), 3.41(t, pyridin-4-yl- 2H), 2.98(m, 2H), 2.78 guanidine (m,1H), 2.58(m, 2H), 1.98(m, 1H), 1.56(m, 7H) 121 SBR-11-4499 N-[4-(4-(CD₃OD, ppm): 8.51(d, 482.28 483.3 505.3 Benzhydryloxy- 2H), 7.70(bs,2H), 7.18- (M + 23) piperidin-1-yl)- 7.45(m, 10H), 5.60(s,butyl]-N′-cyano-N″- 1H), 3.55(t, 2H), 3.42(m, pyridin-4-yl- 1H), 3.15(m,2H), 2.95 guanidine (m, 1H), 2.15(m, 1H), 1.72(m, 11H) 122 SBR-11-4500N-[4-(4- (CD₃OD, ppm): 8.50(s, 482.28 483.3 505.3 Benzhydryloxy- 1H),8.40(d, 1H), 7.80(d, (M + 23) piperidin-1-yl)- 1H), 7.15-7.55(m, 11H),butyl]-N′-cyano-N″- 5.60(s, 1H), 3.54(t, 2H), pyridin-3-yl- 3.42(m, 1H),3.14(m, guanidine 2H), 2.96(m, 1H), 2.14 (m, 1H), 1.70(m, 11H) 123SBR-11-4531 N-(2-{4-[(4-Chloro- (CD₃OD, ppm): 8.39(d, 488.21 489.3 511.3phenyl)-phenyl- 2H), 7.20-7.50(m, 11H), (M + 23) methoxy]-piperidin-5.59(s, 1H), 3.52(m, 1H), 1-yl}-ethyl)-N′- 3.48(t, 2H), 2.86(m, 2H),cyano-N″-pyridin-4- 2.60(t, 2H), 2.32(m, 2H), yl-guanidine 1.91(m, 2H),1.73(m, 2H) 124 SBR-11-4532 N-(3-{4-[(4-Chloro- (CD₃OD, ppm): 8.38(d,502.22 503.2 525.2 phenyl)-phenyl- 2H), 7.20-7.50(m, 11H), (M + 23)methoxy]-piperidin- 5.56(s, 1H), 3.50(m, 1H), 1-yl}-propyl)-N′- 3.45(t,2H), 2.78(m, 2H), cyano-N″-pyridin-4- 2.46(t, 2H), 2.27(m, 2H),yl-guanidine 1.85(m, 2H), 1.81(m, 2H), 1.71(m, 2H) 125 SBR-11-4533N-(4-{4-[(4-Chloro- (CD₃OD, ppm): 8.36(d, 516.24 517.3 539.2phenyl)-phenyl- 2H), 7.20-7.45(m, 11H), (M + 23) methoxy]-piperidin-5.58(s, 1H), 3.49(m, 1H), 1-yl}-butyl)-N′- 3.38(t, 2H), 2.81(m, 2H),cyano-N″-pyridin-4- 2.43(t, 2H), 2.28(m, 2H), yl-guanidine 1.90(m, 2H),1.73(m, 2H), 1.61(m, 4H) 126 SBR-11-4537 N-Cyano-N′-{2-[4- (CD₃OD, ppm):8.38(d, 468.26 469.4 491.3 (phenyl-p-tolyl- 2H), 7.10-7.50(m, 11H), (M +23) methoxy)-piperidin- 5.56(s, 1H), 3.55(m, 1H), 1-yl]-ethyl}-N″-3.50(t, 2H), 2.90(m, 2H), pyridin-4-yl- 2.65(t, 2H), 2.36(m, 2H),guanidine 2.30(s, 3H), 1.92(m, 2H), 1.75(m, 2H) 127 SBR-11-4538N-Cyano-N′-{3-[4- (CD₃OD, ppm): 8.36(d, 482.28 483.4 505.4(phenyl-p-tolyl- 2H), 7.08-7.45(m, 11H), (M + 23) methoxy)-piperidin-5.51(s, 1H), 3.45(m, 1H), 1-yl]-propyl}-N″- 3.41(t, 2H), 2.76(m, 2H),pyridin-4-yl- 2.45(t, 2H), 2.28(s, 3H), guanidine 2.21(m, 2H), 1.86(m,2H), 1.79(m, 2H), 1.69 (m, 2H) 128 SBR-11-4539 N-Cyano-N′-{4-[4- (CD₃OD,ppm): 8.36(d, 496.3 497.4 519.4 (phenyl-p-tolyl- 2H), 7.05-7.45(m, 11H),(M + 23) methoxy)-piperidin- 5.53(s, 1H), 3.49(m, 1H), 1-yl]-butyl}-N″-3.39(t, 2H), 2.79(m, 2H), pyridin-4-yl- 2.41(t, 2H), 2.29(s, 3H),guanidine 2.22(m, 2H), 1.90(m, 2H), 1.70(m, 2H), 1.60 (m, 4H) 129SBR-11-4541 N-[3-(4- (CD₃OD, ppm): 8.32(d, 482.28 483.4 505.3Benzhydryloxymethyl- 2H), 7.15-7.55(m, 12H), (M + 23) piperidin-1-yl)-5.33(s, 1H), 3.42(t, 2H), propyl]-N′-cyano-N″- 3.26(d, 2H), 2.95(d, 2H),pyridin-4-yl- 2.43(t, 2H), 1.98(m, 2H), guanidine 1.80(m, 2H), 1.71(d,2H), 1.65(m, 1H), 1.32 (m, 2H) 130 SBR-11-4542 N-[4-(4- (CD₃OD, ppm):8.36(d, 496.3 497.4 519.3 Benzhydryloxymethyl- 2H), 7.15-7.45(m, 12H),(M + 23) piperidin-1-yl)- 5.34(s, 1H), 3.40(t, 2H), butyl]-N′-cyano-N″-3.29(d, 2H), 3.00(d, 2H), pyridin-4-yl- 2.43(t, 2H), 2.07(m, 2H),guanidine 1.78(d, 2H), 1.70(m, 1H), 1.61(m, 4H), 1.38 (m, 2H) 131SBR-11-4545 N-(2-{4-[Bis-(4- (CD₃OD, ppm): 8.38(d, 522.17 523.2 545.1chloro-phenyl)- 2H), 7.40(d, 2H), 7.32 (M + 23) methoxy]-piperidin- (m,8H), 5.59(s, 1H), 3.55 1-yl}-ethyl)-N′- (m, 1H), 3.48(t, 2H), 2.85cyano-N″-pyridin-4- (m, 2H), 2.60(t, 2H), 2.33 yl-guanidine (m, 2H),1.91(m, 2H), 1.73(m, 2H) 132 SBR-11-4546 N-(3-{4-[Bis-(4- (CD₃OD, ppm):8.37(d, 536.19 536.9 559.0 chloro-phenyl)- 2H), 7.25-7.40(m, 10H), (M +23) methoxy]-piperidin- 5.56(s, 1H), 3.48(m, 1H), 1-yl}-propyl)-N′-3.43(t, 2H), 2.76(m, 2H), cyano-N″-pyridin-4- 2.45(t, 2H), 2.22(m, 2H),yl-guanidine 1.88(m, 2H), 1.80(m, 2H), 1.68(m, 2H) 133 SBR-11-4547N-(4-{4-[Bis-(4- (CD₃OD, ppm): 8.37(d, 550.2 551 573.1 chloro-phenyl)-2H), 7.25-7.40(m, 10H), (M + 23) methoxy]-piperidin- 5.58(s, 1H),3.46(m, 2H), 1-yl}-butyl)-N′- 3.39(t, 2H), 2.79(m, 2H),cyano-N″-pyridin-4- 2.41(t, 2H), 2.25(m, 2H), yl-guanidine 1.89(m, 2H),1.70(m, 2H), 1.60(m, 4H) 134 SBR-11-4561 N-(2-{4-[Bis-(4- (CD₃OD, ppm):8.30(d, 536.19 537.1 558.7 chloro-phenyl)- 2H), 7.46(d, 2H), 7.05 (M +23) methoxymethyl]- (m, 8H), 5.11(s, 1H), 3.67 piperidin-1-yl}- (t, 2H),3.48(m, 2H), 3.20 ethyl)-N′-cyano-N″- (m, 2H), 3.07(m, 2H),pyridin-4-yl- 2.80(m, 2H), 1.75(m, guanidine 3H), 1.45(m, 2H) 135SBR-11-4562 N-(3-{4-[Bis-(4- (CD₃OD, ppm): 8.33(d, 550.2 550.9 573.1chloro-phenyl)- 2H), 7.36(d, 2H), 7.30 (M + 23) methoxymethyl]- (m, 8H),5.32(s, 1H), 3.43 piperidin-1-yl}- (t, 2H), 3.24(d, 2H), 2.95propyl)-N′-cyano-N″- (d, 2H), 2.44(t, 2H), 1.98 pyridin-4-yl- (m, 2H),1.83(m, 2H), guanidine 1.71(m, 2H), 1.65(m, 1H), 1.33(m, 2H) 136SBR-11-4563 N-(4-{4-[Bis-(4- (CD₃OD, ppm); 8.36(d, 564.22 565chloro-phenyl)- 2H), 7.30(m, 10H), 5.32 methoxymethyl]- (s, 1H), 3.40(t,2H), 3.26 piperidin-1-yl}- (d, 2H), 2.95(d, 2H), 2.38butyl)-N′-cyano-N″- (t, 2H), 1.99(m, 2H), 1.74 pyridin-4-yl- (m, 2H),1.60(m, 5H), guanidine 1.35(m, 2H) 137 SBR-11-4570 N-(2-{4-[Bis-(4-(CD₃OD, ppm): 8.55(d, 490.23 491.2 fluoro-phenyl)- 2H), 7.70(d, 2H),7.40 methoxy]-piperidin- (m, 4H), 7.06(m, 4H), 1-yl}-ethyl)-N′- 5.64(s,1H), 3.60(m, 1H), cyano-N″-pyridin-4- 3.50(t, 2H), 2.90(m, 2H),yl-guanidine 2.62(t, 2H), 2.35(m, 2H), 1.98(m, 2H), 1.75(m, 2H) 138SBR-11-4624 N-(2-{4-[(4-Chloro- (CD₃OD, ppm): 8.38(d, 473.21 474.2 496.2phenyl)-phenyl- 2H), 7.15-7.45(m, 11H), (M + 23) methyl]-piperazin-1-4.32(s, 1H), 3.48(t, 2H), yl}-ethyl)-N′-cyano- 2.62(m, 6H), 2.45(m,N″-pyridin-4-yl- 4H) guanidine 139 SBR-11-4625 N-(3-{4-[(4-Chloro-(CD₃OD, ppm): 8.39(d, 487.23 488.2 510.2 phenyl)-phenyl- 2H),7.20-7.45(m, 11H), (M + 23) methyl]-piperazin-1- 4.22(s, 1H), 3.43(t,2H), yl}-propyl)-N′-cyano- 2.47(m, 10H), 1.80(m, N″-pyridin-4-yl- 2H)guanidine 140 SBR-11-4626 N-(4-{4-[(4-Chloro- (CD₃OD, ppm): 8.36(d,501.24 502.2 524.2 phenyl)-phenyl- 2H), 7.10-7.45(m, 11H), (M + 23)methyl]-piperazin-1- 4.24(s, 1H), 3.39(t, 2H), yl}-butyl)-N′-cyano-2.58(m, 4H), 2.46(m, N″-pyridin-4-yl- 6H), 1.61(m, 4H) guanidine 141SBR-11-4633 N-[2-(4-Benzyl- (CD₃OD, ppm): 8.56(d, 363.22 364.2 386.1piperazin-1-yl)- 2H), 7.51(m, 7H), 3.51(s, (M + 23) ethyl]-N′-cyano-N″-2H), 3.43(t, 2H), 2.55(m, pyridin-4-yl- 10H) guanidine 142 SBR-11-4634N-[2-(4- (CD₃OD, ppm): 8.37(d, 407.21 408.2 430.2 Benzo[1,3]dioxol-5-2H), 7.40(d, 2H), 6.84(s, (M + 23) ylmethyl-piperazin-1- 1H), 6.76(s,2H), 5.93(s, yl)-ethyl]-N′-cyano- 2H), 3.51(t, 2H), 3.48(s,N″-pyridin-4-yl- 2H), 2.62(m, 10H) guanidine 143 SBR-11-4638N-[3-(4-Benzyl- (CD₃OD, ppm): 8.38(d, 377.23 378.2 400.2piperazin-1-yl)- 2H), 7.35(d, 2H), 7.31 (M + 23) propyl]-N′-cyano-N″-(m, 5H), 3.54(s, 2H), 3.45 pyridin-4-yl- (t, 2H), 2.55(m, 8H), 2.50guanidine (t, 2H), 1.82(m, 2H) 144 SBR-11-4639 N-[3-(4- (CD₃OD, ppm):8.39(d, 421.22 422.2 444.2 Benzo[1,3]dioxol-5- 2H), 7.38(d, 2H), 6.83(s,(M + 23) ylmethyl-piperazin-1- 1H), 6.75(s, 2H), 5.92(s,yl)-propyl]-N′-cyano- 2H), 3.47(t, 2H), 3.44(s, N″-pyridin-4-yl- 2H),2.47(m, 10H), 1.81 guanidine (m, 2H) 145 SBR-11-4419 N-[2-(2-Benzhydryl-(CDCl₃, ppm): 8.15(d, 415.2 416.4 438.3 oxyethoxy)ethyl]-N′- 2H),7.23-7.44(m, 13H), (M + 23) cyano-N″-pyridin-4- 7.05(br s, 1H), 5.36(s,yl-guanidine 1H), 3.61-3.82(m, 8H) 146 SBR-11-4438 3-{2-[2-(N′-cyano-(CD₃OD, ppm): 8.27(d, 378.1 379.3 401.3 N″-pyridin-4-yl- 2H), 7.72(m,4H), 7.25 (M + 23) guanidino)-ethoxy]- (d, 2H), 3.89(t, 2H), 3.84ethyl}-1,1-diphenyl- (t, 2H), 3.71(t, 2H), 3.52 urea (t, 2H) 147SBR-11-4442 N-{2-[2-(4-Methoxy- (CDCl₃, ppm): 8.44(d, 385.16 386.2 408.2benzylsulfanyl)- 2H), 7.46(d, 2H), 7.19 (M + 23) ethoxy]-ethyl}-N′- (d,2H), 7.02(br s, 1H), cyano-N″-pyridin-4- 6.85(br s, 1H), 6.84(d,yl-guanidine 2H), 3.79(s, 3H), 3.55- 3.82(m, 8H), 2.67(t, 2H) 148SBR-11-4439 Naphthalene-1- (CD₃OD, ppm): 8.68(d, 438.15 439.3 461.3sulfonic acid {2-[2- 1H), 8.33(d, 2H), 8.22 (N′-cyano-N″- (d, 1H),8.15(d, 1H), pyridin-4-yl- 8.00(d, 1H), 7.58(m, guanidino)-ethoxy]- 3H),7.30(d, 2H), 3.41(t, ethyl}-amide 2H), 3.37(m, 4H), 3.09 (t, 2H)

EXAMPLE 149 In vitro efficacy studies

In the primary screening, the test compounds were applied to a panel offive human cell lines at a concentration of 12.5 μM. From the resultsobtained from this primary screening, cytotoxic compounds were selectedto apply to a panel of 27 cell lines at a range of differentconcentrations in the secondary screening. The concentration of a testcompound that produces a cytotoxicity level of 50% (IC₅₀) wasdetermined.

In the primary screening, clonogenic assay was used. Cells were seededat a low cell density in 96 well flat-bottom plates and incubated for 24hours at 37° C. in a 7% CO₂ atmosphere. The 5 cell lines used were: CX-1(colon carcinoma), MDA-MB-435 (breast carcinoma), PC-3 (prostatecarcinoma), H2 (leukemia), and CCD-39sk (normal skin fibroblasts). Testcompounds at 12.5 μM were then added in duplicate to the cell plates andincubated for 6 days under the same conditions. MTS colorimetric assay(Promega), which measures cell viability based on the cellularconversion of a tetrazolium salt, was performed is directly in the 96well plates at the end of the 6-day period. After the plates were readand recorded, viable adherent cells were stained with Crystal violet(Sigma) to verify the results obtained from the MTS assay.

In the secondary screening, IC₅₀ values were determined. Cells wereseeded at a low cell density in 96 well flat-bottom plates and incubatedfor 24 hours at 37° C. in a 7% CO₂ atmosphere. Cell lines used in thisscreening were: CX-1 (colon carcinoma), MIP-101 (colon carcinoma),HCT-116 (colon carcinoma), HCT-29 (colon carcinoma), HCT-15 (coloncarcinoma), MDA-MB-435 (breast carcinoma), MCF-7 (breast carcinoma),PC-3 (prostate carcinoma), DU-145 (prostate carcinoma), H2 (leukemia),K562 (leukemia), HL-60 (leukemia), RL (non-Hodgkin's B cell lymphoma),A549 (lung carcinoma), H510A (small cell lung carcinoma), ME-180(cervical carcinoma), HeLa (cervical carcinoma), 2008 (cervicalcarcinoma), C13 (cervical carcinoma, CDDP resistant), ES-2 (ovariancarcinoma), MIA PaCa2 (pancreatic carcinoma), ACHN (renaladenocarcinoma), HepG2 (liver carcinoma), LOX (melanoma), G3361(melanoma), CCD-39sk (normal skin fibroblasts), and CV-1 (transformedmonkey kidney cells). Test compounds were added in duplicate in serialdilution from 0.005 to 10.0 μM to the cell plates. The cell plates werethen incubated for 6 days under the same conditions. MTS assay wasperformed followed by staining of viable adherent cells with Crystalviolet after the 6-day period. The results obtained from Crystal violetstained plates were used to compare and verify those obtained from theMTS assay.

Seventy of the one hundred thirty eight cyanoguanidine compounds testedwere shown to have an IC₅₀ value of less than 5 μM towards RL(non-Hodgkin's lymphoma) cells, and five compounds demonstrated an IC₅₀value of less than 0.005 μM. For CX-1 (colon carcinoma) cells, twentyfour compounds tested were shown to have an IC₅₀ values of less than 5μM and the IC₅₀ values of nine compounds were less than 0.005 μM. ForDU-145 (prostate carcinoma) cells, sixteen compounds were shown to havean IC₅₀ value of less than 5 μM and two compounds demonstrated an IC₅₀value less than 0.005 μM.

Several test compounds were shown to selectively target tumor cells incomparison to normal cells. For example, when comparing the IC₅₀ valuesobtained from using a normal cell line (CV-1) with those obtained fromusing a tumor cell line (PC-3), twenty cyanoguanidine compounds wereshown to have a >50-fold selectivity of tumor cells and six compoundsunexpectedly demonstrated a selectivity of 1000-fold or more. Forcomparison, Taxol and Etoposide (VP-16), two compounds that arecurrently in clinical use, demonstrated only a 20-fold and 0-foldselectivity, respectively.

EXAMPLE 150 In vivo Efficacy Studies

From the in vitro results obtained, cyanoguanidine compounds wereselected for human tumor xenograft regression assays. Animals bearingestablished tumors (RL) were treated with a test compound for athree-week period. The growth of the tumors and the general health ofthe animals were monitored during the treatment and for an additionaltwo weeks after dosing had been terminated to determine if tumorregrowth took place.

Non-Hodgkin's B cell lymphoma (RL) tumor cells, which were adapted togrow as solid tumors, were implanted by an intradermal injection of atumor cell suspension (30×10⁶ cells in 0. 1 mL media) in the flanks offemale NIH Swiss nude mice (Taconic Labs). Each mouse was implanted withone tumor and 6-8 mice per group were used.

Dosing was initiated one week after implantation (Day 1), when tumorsreached approximately 50 to 100 mm³ in volume, with a test compound orvehicle five times per week for three weeks either intravenously (IV) orintraperitoneally (IP). Cyclophosphamide (CTX, Sigma) was used as astandard in the assays. Compounds were first dissolved in DMSO (Sigma)and formulated with 20% Cremophor RH40 (BASF) to a final concentrationof 10% DMSO/18% Cremophor. The formulated solution was made fresh daily.

Tumors, assumed to be hemi-ellipsoid in shape, were measured withcalipers in three dimensions. Tumor volumes were calculated using theequation:

Volume=112 (L/2×W12×H) 4/3 π

where L=length, W=width, and H=height of the tumor. Animals were weighedand their general health was monitored during the course of the assay.When tumors became necrotic or if animals became moribund, the animalswere euthanized by CO₂ asphyxiation. Student's t test was used todetermine if there was a significant difference between the dataobtained in the compound treated group and the vehicle treated group.

In a preliminary RL tumor growth regression assay, eight compounds wereadministered twice a day (via IV route in the morning and IP route inthe afternoon) for five days per week for a three-week period. Five ofthe eight compounds completely regressed all tumors within the first twoweeks of the dosing period. Four of these compounds, SBR-11-2780 (75mg/kg), SBR-11-2889 (90 mg/kg), SBR-11-2897 (75 mg/kg), SBR-11-2900 (60mg/kg), showed little gross toxicity and the animals receiving thecompounds had less than 10% weight loss. One compound, SBR-11-2727 (60mg/kg), showed signs of gross toxicity within the first week and dosingwas reduced to once per day. For comparison, cyclophosphamide, reducedthe average tumor volume to 2% of control by Day 18. The remaining threecompounds also demonstrated efficacy in the RL tumor xenograph model.Compounds SBR-11-2899 (75 mg/kg), SBR-11-2750 (75 mg/kg), andSBR-11-2749 (75 mg/kg) reduced the average tumor volume to 10%, 14%, and18% of the tumor volume obtained in the control on Day 21, respectively.One compound, SBR-11-4483 (60 mg/kg) was administered once per day (viaIV route) for a two-week period. By day 19, a reduction of the averagetumor volume to 1% was observed. The test animals showed less than 10%weight loss. All compounds tested were able to significantly reducetumor volumes in comparison to the results obtained in the vehicletreated controls (p<0.05).

The ability of compounds to act in a dose dependent manner was assayedin an RL tumor growth regression assay using compounds SBR-11-2897 andSBR-11-2780. SBR-11-2780 demonstrated a dose dependent effect: tumorvolumes were reduced to 86%, 24%, and 3% of the average tumor volumesobtained in the control group with doses of 20, 40, and 80 mg/kg,respectively. All three doses of SBR-11-2897 resulted in an almostcomplete reduction of average tumor volumes relative to vehicle treatedcontrols (4 to 6% of control). Less than 10% weight loss was observedfor all mice except for one mouse from the CTX-treated group.

EXAMPLE 151 Acute Toxicity Studies

Female SW mice with body weights over 20 g were used in the acutetoxicity study. The mice were divided into three groups: untreated,treated with vehicle, and treated with a test cyanoguanidine compound.Three mice were assigned to each group and were given doses by a singleintravenous bolus administration. The highest doses tested producedacute lethal or significantly toxic effects. The experiment lasted forone week. The mortality, clinical signs of toxicity, and body weight ofeach animal were monitored and recorded every day or every other day.Necropsy and gross examinations of major organs were performed on theanimals which died during the study as well as those sacrificed at theend of the experiment. Histopathogical evaluations were conducted on 2-3Hematoxylin and Eosin stained tissue sections from major organsincluding the heart, liver, kidneys, lungs and spleen, of the animalswhich died or were treated with the highest dose of the test compound.

The lethal doses of the compounds shown in Examples 1-148 above, whichis defined as causing 1/3 animal deaths, were determined to be about 150to about 200 mg/kg. SBR-11-2897 and SBR-11-4483 were each administeredto three animals at the doses of 200, 150, and 100 mg/kg, respectively.All animals survived.

EXAMPLE 152 Preliminary Sub-acute Toxicity Studies

The preliminary sub-acute toxicity study was carried out in parallel onthe same animals used in the efficacy study (see Example 150). Aftercontinuous treatment for 3 weeks with repeated intravenous andintraperitoneal dosing, three out of eight animals were sacrificed ineach treatment group. The remaining animals were sacrificed two weekslater. Necropsy, liver weight, gross examinations of visibleabnormalities in the major organs, and limited histological studies wereconducted in all animals. In addition, blood chemistry tests andcomplete blood cell count analyses were performed in most of theanimals.

In the sub-acute toxicity study, a repeated dosing of about 150 to 180mg/kg/day (i.v.+i.p.) for 3 weeks was well tolerated by the animals. Thetoxicity observed in the animals treated with SBR-11-2897 at the totaldose of 150 mg/kg/day (i.v.+i.p.) for 3 weeks included only a mildreduction of the total white blood cell count and increased blood AST(aspartate aminotransferase) and ALT (alanine aminotransferase) levelsin 1/3 animals with a moderate reduction in the size of the white pulpin the spleen and very mild mononuclear cell aggregates in the liver.The toxicity observed in the animals treated with SBR-11-4483 at thetotal dose of 60 or 120 mg/kg/day (i.v.) for two weeks includeddose-dependent behavioral changes, moderate dose-dependent decreases inbody weight at the dose of 120 mg/kg, mild increases of blood ALT andAST levels, along with some histopathological changes such as mild lungcongestion with mild inflammatory cell infiltrates at the does of 120mg/kg, mild and focal mononuclear cell aggreates in the liver with a fewdegenerated/apototic hapatocytes at 60 mg/kg, and a small focalwell-circumscribed necrosis with minimal inflammatory infiltrate in theliver at 120 mg/kg.

OTHER EMBODIMENT

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

What is claimed is:
 1. A compound of the following formula:

wherein R¹ is 3-pyridyl, 4-pyridyl, or quinolinyl, optionallysubstituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl,alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino,aminosulfonyl, sulfonic acid, or alkylsulfonyl; each of R² and R³,independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, thioalkyl,aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino,or aminocarbonyl; L¹ is —X¹—Y¹—X²— in which each of X₁ and X²,independently, is a bond, or a C₁₋₆ alkylene chain optionally containinga double bond or a triple bond and further optionally substituted withalkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino,alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl,alkylcarbonylamino, or aminocarbonyl; and Y¹ is —O—, —S—, —SO—, —SO₂—,—N(R^(a))—, —CO—, —N(R^(a))—CO—, —CO—N(R^(a))—, —N(R^(a))—CO—CO—,—N(R^(a))—SO₂—, —SO₂—N(R^(a))—, —N(R^(a))—CO—O—, —O—CO—N(R^(a))—,—N(R^(a))—CO—N(R^(b))—, —N(R^(a))—CS—N(R^(b))—CO—,—CO—N(R^(a))—CS—N(R^(b))—, —O—CO—, —CO—O—, —O—SO₂—, —SO₂—O—,—O—S—CO—N(R^(a))—, —N(R^(a))—CO—S—O—, —O—CO—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond;each of R^(a) and R^(b), independently, being hydrogen, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; R⁴ is aryl, optionally substituted with alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino,aminioalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl,formyl, oxo, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino,aminosulfonyl, sulfonic acid, or alkylsulfonyl; L² is —X³—Y²—X⁴— inwhich each of X³ and X⁴, independently, is a bond, or a C₁₋₆ alkylenechain optionally containing a double bond or a triple bond and furtheroptionally substituted with alkoxy, hydroxyl, halo, carboxyl, amino,nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl,alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl; and Y² is—O—, —S—, —SO—, —SO₂—, —N(R^(c)), —CO—, —N(R^(c))—CO—, —CO—N(R^(c))—,—N(R^(c))—CO—CO—, —N(R^(c))—SO₂—, —SO₂—N(R^(c))—, —N(R^(c))—CO—O—,—O—CO—N(R^(c))—, —N(R^(c))—CO—N(R^(d))—, —N(R^(c))—CS—N(R^(d))—CO—,—CO—N(R^(c))—CS—N(R^(d))—, —O—CO—, —CO—O—, —O—, SO₂—, —SO₂—O—,—O—S—CO—N(R^(c))—, —N(R^(c))—CO—S—O—, —O—CO—O—,—CO—N(R^(c))—S—CO—N(R^(d))—, —N(R^(c))—CO—S—N(R^(d))—CO— or a bond; eachof R^(c) and R^(d), independently, being hydrogen, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; and R⁵ is cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, or heteroaryl, optionally substituted withalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy,aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxyalkyl, aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo,aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl,aminocarbonyloxy, or alkyloxycarbonylamino; provided that each of Y¹ andY² is not a bond simultaneously; and that when neither Y¹ nor Y² is abond, at least one of X², R⁴, and X³ is not a bond; or an N-oxidederivative or a salt thereof.
 2. The compound of claim 1, wherein R¹ isunsubstituted 4-pyridyl.
 3. The compound of claim 1, wherein each of R²and R³, independently, is hydrogen.
 4. The compound of claim 1, whereinY¹ is —SO—, —SO₂—, —N(R^(a))—CO—CO—, —N(R^(a))—SO₂—, —SO₂—N(R^(a))—,—N(R^(a))—CO—N(R^(b))——N(R^(a))—CS—N(R^(b))—CO—,—CO—N(R^(a))—CS—N(R^(b))—, —O—SO₂—, —SO₂—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond. 5.The compound of claim 1, wherein Y² is —SO—, —SO₂—, —N(R^(a))—CO—CO—,—N(R^(a))—SO₂—, —SO₂—N(R^(a))—, —N(R^(a))—CO—N(R^(b))—,—N(R^(a))—CS—N(R^(b))—CO—, —CO—N(R^(a))—CS—N(R^(b))—, —O—SO₂—, —SO₂—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond. 6.The compound of claim 1, wherein neither one of Y¹ and Y² is a bond. 7.The compound of claim 6, wherein R⁵ is phenyl or naphthyl, optionallysubstituted with alkyl, alkoxy, amino, or halo.
 8. The compound of claim7, wherein R¹ is unsubstituted 4-pyridyl, and each of R² and R³,independently, is hydrogen.
 9. The compound of claim 8, wherein X¹ is aC₁₋₄ alkylene chain, Y¹ is —O—, —S—, —O—CO—, —N(R^(a))—, —N(R^(a))—CO—,or —N(R^(a))—CO—N(R^(b))—, in which each of R^(a) and R^(b),independently, is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, orheteroaralkyl, and X² is a bond.
 10. The compound of claim 9, wherein X³is a C₁₋₄ alkylene chain, Y² is —O—, —S—, —O—CO—, —N(R^(c))—,—N(R^(c))—CO—, or —N(R^(c))—CO—N(R^(d))—, in which each of R^(c) andR^(d), independently, is alkyl, alkylcarbonyl, aryl, heteroaryl,aralkyl, or heteroaralkyl, and X⁴ is a bond or a C₁₋₂ alkylene chainoptionally substituted with aryl, heteroaryl, aralkyl, or heteroaralkyl.11. The compound of claim 1, wherein Y¹ is a bond.
 12. The compound ofclaim 11, wherein X¹ is a C₁₋₂ alkylene chain, and X² is a bond or aC₁₋₂ alkylene chain.
 13. The compound of claim 11, wherein X³ is a bondor a C₁₋₄ alkylene chain optionally containing a double bond, Y² is —O—,—S—, —SO₂—, —N(R^(c))—, —N(R^(c))—CO—, —N(R^(c))—CO—CO—,—N(R^(c))—CO—O—, —N(R^(c))—SO₂—, —N(R^(c))—CS—N(R^(d))—CO—,—N(R^(c))—CO—S—N(R^(d))—CO—, —N(R^(c))—CO—S—O—, or—N(R^(c))—CO—N(R^(d))—, in which each of R^(c) and R^(d), independently,is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,and X⁴ is a bond or a C₁₋₄ alkylene chain optionally substituted witharyl, heteroaryl, aralkyl, or heteroaralkyl.
 14. The compound of claim11, wherein R⁴ is phenyl.
 15. The compound of claim 11, wherein R⁵ isaryl or heteroaryl.
 16. The compound of claim 15, wherein R⁵ is phenyl,naphthyl, indolyl, or chromanyl, optionally substituted with alkyl,aralkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkoxy, amino, halo, orhaloalkyl.
 17. The compound of claim 16, wherein R¹ is unsubstituted4-pyridyl, and each of R² and R³, independently, is hydrogen.
 18. Thecompound of claim 17, wherein X¹ is a C₁₋₂ alkylene chain, Y¹ is a bond,and X² is a bond or a C₁₋₂ alkylene chain.
 19. The compound of claim 18,wherein X³ is a bond or a C₁₋₂ alkylene chain optionally containing adouble bond, Y² is —O—, —SO₂—, —N(R^(c))—SO₂—, —N(R^(c))—CO—,—N(R^(c))—CO—N(R^(d))—, or a bond, and X⁴ is a bond or a C₁₋₂ alkylenechain optionally substituted with aryl, heteroaryl, aralkyl, orheteroaralkyl.
 20. The compound of claim 19, wherein R⁵ is phenyl ornaphthyl, optionally substituted with alkyl, aralkyl, alkoxy, amino,halo, or haloalkyl.
 21. The compound of claim 20, wherein R⁴ is phenyl,X³ is a bond, and Y² is —N(R^(c))—CO— or —N(R^(c))—SO₂—.
 22. Thecompound of claim 21, where the compound is5-dimethylamino-naphthalene-1-sulfonic acid(4-(N′-cyano-″-pyridin-4-yl-guanidinomethyl)-phenyl)-amide,naphthalene-1-sulfonic acid(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-amide,N-(4-(N′-cyano-N″-pyridin-4-yl-guanidino-methyl)-phenyl)-3-trifluoromethyl-benzenesulfonamide,2,4,6-trimethyl-N-(4-(N′-cyano-N″-pyridin-4-yl-guani-dinomethyl)-phenyl)-benzenesulfonamide,or4-chloro-N-(4-(N′-cyano-N″-pyridin-4-yl-guanidinomethyl)-phenyl)-benzenesulfonamide.23. A compound of the following formula:

wherein R¹ is 3-pyridyl, 4-pyridyl, or quinolinyl, optionallysubstituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo,haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl,alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino,aminosulfonyl, sulfonic acid, or alkylsulfonyl; each of R² and R³,independently, is H, alkyl, alkoxy, hydroxylalkyl, thioalkyl,aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino,or aminocarbonyl; L¹ is —X¹—Y¹—X²— in which each of X¹ and X²,independently, is a bond, or a C₁₋₆ alkylene chain optionally containinga double bond or a triple bond and further optionally substituted withalkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro,cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl,alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl,formyl, alkylcarbonylamino, or aminocarbonyl; and Y¹ is —O—, —S—, —SO—,—SO₂—, —N(R^(a))—, —CO—, —N(R^(a))—CO—, —CO—N(R^(a))—, —N(R^(a))—CO—CO—,—N(R^(a))—SO₂—, —SO₂—N(R_(a))—,—N(R^(a))—CO—O—, —O—CO—N(R^(a))—,—N(R^(a))—CO—N(R^(b))—, —N(R^(a))—CS—N(R^(b))—CO—,—CO—N(R^(a))—CS—N(R^(b))—, —O—CO—, —CO—O—, —O—SO₂—, —SO₂—O—,—O—S—CO—N(R^(a))—, —N(R^(a))—CO—S—O—, —O—CO—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond;each of R^(a) and R^(b), independently, being H, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; R⁴ is a bond, or cycloalkyl, cycloalkenyl, or aryl,optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl,carboxyl, halo, haloalkyl, amino, aminioalkyl, nitro, cyano, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkylcarbonyloxy,alkyloxycarbonyl, alkylcarbonyl, formyl, oxo, alkylcarbonylamino,aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, oralkylsulfonyl; L² is —X³—Y²—X⁴— in which each of X³ and X⁴,independently, is a bond, or a C₁₋₆ alkylene chain optionally containinga double bond or a triple bond and further optionally substituted withalkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro,cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl,alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl,formyl, alkylcarbonylamino, or aminocarbonyl; and Y² is —O—, —S—, —SO—,-SO₂—, —N(R^(c))—, —CO—, —N(R^(c))—CO—, —CO—N(R^(c))—, —N(R^(c))—CO—CO—,—N(R^(c))—SO₂—, —SO₂—N(R^(c))—, —N(R^(c))—CO—O—, —O—CO—N(R^(c))—,—N(R^(c))—CO—N(R^(d))—, —N(R^(c))—CS—N(R^(d))—CO—,—CO—N(R^(c))—CS—N(R^(d))—, —O—CO—, —CO—O—, —O—SO₂—, —SO₂——,—O—S—CO—N(R^(c))—, —N(R^(c))—CO—S—O—, —O—CO—O—,—CO—N(R^(c))—S—CO—N(R^(d))—, —N(R^(c))—CO—S—N(R^(d))—CO—, or a bond;each of R^(c) and R^(d), independently, being H, alkyl, alkoxy,hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; and R⁵ is a cyclic moiety having 12-20 ring atoms,optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl,carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy,heteroaryloxy, aralkoxy, heteroaralkoxy, alkylcarbonyloxy,alkyloxycarbonyl, arylcarbonyloxyalkyl, aryloxycarbonylalkyl,alkylcarbonyl, formyl, oxo, aminocarbonyl, alkylcarbonylamino,alkylsulfonylamino, aminosulfonyl, aminocarbonyloxy, oralkyloxycarbonylamino; provided that when neither one of Y¹ and Y² is abond, at least one of X², R⁴, and X³ is not a bond; or an N-oxidederivative or a salt thereof.
 24. The compound of claim 23, wherein R¹is unsubstituted 4-pyridyl, and each of R² and R³, independently, ishydrogen.
 25. The compound of claim 23, wherein Y¹ is —SO—, —SO₂—,—N(R^(a))—CO—CO—, —N(R^(a))—SO₂—, —SO₂—N(R^(a))—,—N(R^(a))—CO—N(R^(b))—, —N(R^(a))—CS—N(R^(b))—CO—,—CO—N(R^(a))—CS—N(R^(b))—, —O—SO₂—, —SO₂—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond. 26.The compound of claim 23, wherein Y² is —SO—, —SO²—, —N(R^(a))—CO—CO—,—N(R^(a))—SO₂—, —SO₂—N(R^(a))—, —N(R^(a))—CO—N(R^(b))—,—N(R^(a))—CS—N(R^(b))—CO—, —CO—N(R^(a))—CS—N(R^(b))—, —O—SO₂—, —SO₂—O—,—CO—N(R^(a))—S—CO—N(R^(b))—, —N(R^(a))—CO—S—N(R^(b))—CO—, or a bond. 27.The compound of claim 23, wherein R⁵ is optionally substituted withalkyl, aralkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkoxy, amino, halo,or haloalkyl.
 28. The compound of claim 27, wherein R¹ is unsubstituted4-pyridyl, each of R² and R³, independently, is hydrogen.
 29. Thecompound of claim 28, wherein each of X¹ and X², independently, is abond or a C₁₋₂ alkylene chain, and Y¹ is a bond.
 30. The compound ofclaim 29, wherein each of X³ and X⁴, independently, is a bond or a C₁₋₄alkylene chain, and Y² is —O—, —N(R^(c))—CO—, —N(R^(c))—SO₂—,—N(R^(c))—CO—N(R^(d))—, or a bond.
 31. The compound of claim 30, whereinR⁵ is fluorenyl, dihydrodibenzoazepine, or dibenzocycloheptenyl.
 32. Thecompound of claim 31, wherein R⁴ is a bond.
 33. The compound of claim32, where the compound isN-(5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)pentyl)-N′-cyano-N″-pyridin-4-yl-guanidine.34. The compound of claim 28, wherein neither one of Y¹ and Y² is abond.
 35. The compound of claim 34, wherein X¹ is a C₁₋₄ alkylene chain,Y¹ is —O—, —S—, —O—CO—, —N(R^(a))—, —N(R^(a))—CO—, or—N(R^(a))—CO—N(R^(b))—, in which each of R^(a) and R^(b), independently,is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,and X² is a bond.
 36. The compound of claim 35, wherein X³ is a C₁₋₄alkylene chain, Y² is —O—, —S—, —O—CO—, —N(R^(c))—, —N(R^(c))—CO—, or—N(R^(c))—CO—N(R^(d))—, in which each of R^(c) and R^(d), independently,is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,and X⁴ is a bond or a C₁₋₂ alkylene chain optionally substituted witharyl, heteroaryl, aralkyl, or heteroaralkyl.
 37. The compound of claim36, wherein R⁴ is a bond.
 38. The compound of claim 37, wherein R⁵ isfluorenyl, dihydrodibenzoazepine, or dibenzocycloheptenyl.
 39. Thecompound of claim 38, where the compound isN-{2-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethoxy]-ethyl}-N′-cyano-N″-pyridin-4-yl-guanidineorN-[2-(10,11-dihydro-5H-dibenzo[ad]cyclohepten-5-yloxy)-ethyl]-N-[2-(N′-cyano-N″-pyridin-4yl-guanidino)-ethyl]-acetamide.